Anti-tau antibodies and uses thereof

ABSTRACT

Provided herein are antibodies that specifically bind Tau and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/030,655, filed Sep. 24, 2020, which is a continuation of U.S.application Ser. No. 16/161,586, filed Oct. 16, 2018, issued as U.S.Pat. No. 10,829,547, which claims the benefit of U.S. Application No.62/572,910, filed Oct. 16, 2017; U.S. Application No. 62/577,011, filedOct. 25, 2017; and U.S. Application No. 62/697,034, filed Jul. 12, 2018.Each of these applications is incorporated herein by reference in itsentirety. This application also is related to U.S. application Ser. No.16/217,360, filed Dec. 12, 2018, now issued as U.S. Pat. No. 10,358,485.

SEQUENCE LISTING

This application includes a Sequence Listing submitted electronically asa text file named “104018001204_Sequence Listing.xml”, created on Dec.8, 2022 with a size of 1,697,466 bytes. The Sequence Listing isincorporated by reference herein.

TECHNICAL FIELD

The present invention relates to antibodies that specifically bind Tauand methods of using the same.

BACKGROUND

Human Tau is encoded by the microtubule-associated protein Tau gene,MAPT, located on chromosome 17q21. The adult human brain contains sixmain Tau isoforms which are generated by alternative splicing of exon 2(E2), E3, and E10. These isoforms differ depending on the number of29-residue repeat regions near the N-terminus. Tau isoforms containing0, 1, or 2 inserts are known as ON, IN, and 2N, respectively.Unprocessed Tau isoforms also contain either 3 (“3R”) or 4 (“4R”)microtubule-binding repeat domains. The second of these repeat domainsis encoded by E10 and is not included in 3R Tau isoforms (FIG. 1 ).

Although Tau is usually highly soluble, under pathological conditions,it can aggregate into paired helical filaments, neurofibrillary tanglesand other structures that define a large spectrum of neurodegenerativediseases termed Tauopathies. Tauopathy thus refers to a class ofneurodegenerative diseases associated with aggregation of themicrotubule-associated protein Tau, including Alzheimer's disease (AD),progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD).

The underlying mechanism of Tau-mediated neurotoxicity is poorlyunderstood and the trigger for Tau aggregation in neurons is yet to beelucidated. Thus, while therapeutic approaches targeting Tau are beingexplored, there remains a need for specific and effective therapeuticagents that target Tau.

SUMMARY

Provided herein are monoclonal antibodies, or antigen-binding fragmentsthereof, that specifically bind a human Tau isoform or fragment. In someaspects, the antibody is murine antibody, a chimeric antibody, or ahumanized antibody. In some embodiments, the antibody isotype is IgG1.In some embodiments, the antibody comprises: a heavy chaincomplementarity determining region 1 (HCDR1), a heavy chaincomplementarity determining region 2 (HCDR2), and a heavy chaincomplementarity determining region 3 (HCDR3) as set forth in SEQ ID NO:196 and a light chain complementarity determining region 1 (LCDR1), alight chain complementarity determining region 2 (LCDR2), and a lightchain complementarity determining region 3 (LCDR3) as set forth in SEQID NO: 411; a HCDR1, a HCDR2, and a HCDR3 as set forth in SEQ ID NO: 268and a LCDR1, a LCDR2, and a LCDR3 as set forth in SEQ ID NO: 465; or aHCDR1, a HCDR2, and a HCDR3 as set forth in SEQ ID NO: 402 and a LCDR1,a LCDR2, and a LCDR3 as set forth in SEQ ID NO: 572. In someembodiments, the monoclonal antibody or antigen-binding fragment thereofcomprises a HCDR1 comprising SEQ ID NO: 594, a HCDR2 comprising SEQ IDNO: 596, a HCDR3 comprising SEQ ID NO: 598, a LCDR1 comprising SEQ IDNO: 738, a LCDR2 comprising SEQ ID NO: 740, and a LCDR3 comprising SEQID NO: 742 as defined according to the method of Kabat; a HCDR1comprising SEQ ID NO: 864, a HCDR2 comprising SEQ ID NO: 866, a HCDR3comprising SEQ ID NO: 868, a LCDR1 comprising SEQ ID NO: 1008, a LCDR2comprising SEQ ID NO: 1010, and a LCDR3 comprising SEQ ID NO: 1012 asdefined by IMGT; a HCDR1 comprising SEQ ID NO: 642, a HCDR2 comprisingSEQ ID NO: 644, a HCDR3 comprising SEQ ID NO: 646, a LCDR1 comprisingSEQ ID NO: 774, a LCDR2 comprising SEQ ID NO: 776, and a LCDR3comprising SEQ ID NO: 778 as defined according to the method of Kabat; aHCDR1 comprising SEQ ID NO: 912, a HCDR2 comprising SEQ ID NO: 914, aHCDR3 comprising SEQ ID NO: 916, a LCDR1 comprising SEQ ID NO: 1044, aLCDR2 comprising SEQ ID NO: 1046, and a LCDR3 comprising SEQ ID NO: 1048as defined by IMGT; a HCDR1 comprising SEQ ID NO: 732, a HCDR2comprising SEQ ID NO: 734, a HCDR3 comprising SEQ ID NO: 736, a LCDR1comprising SEQ ID NO: 846, a LCDR2 comprising SEQ ID NO: 848, and aLCDR3 comprising SEQ ID NO: 850 as defined according to the method ofKabat; or a HCDR1 comprising SEQ ID NO: 1002, a HCDR2 comprising SEQ IDNO: 1004, a HCDR3 comprising SEQ ID NO: 1006, a LCDR1 comprising SEQ IDNO: 1116, a LCDR2 comprising SEQ ID NO: 1118, and a LCDR3 comprising SEQID NO: 1120 as defined by IMGT.

According to some aspects, the aforementioned monoclonal antibodies orantigen-binding fragments thereof comprise sequence modifications. Insome embodiments, modification(s) is position 49 of the light chainaccording to the method of Kabat is not cysteine, the residue atposition 57 of the heavy chain according to the method of Kabat is notcysteine, the residue at position 34 of the light chain according to themethod of Kabat is glutamate, the residue at position 36 of the lightchain according to the method of Kabat is not phenylalanine, the residueat position 46 of the light chain according to the method of Kabat isnot arginine, the residue at position 94 of the heavy chain according tothe method of Kabat is not lysine, the residue at position 71 of theheavy chain according to the method of Kabat is not arginine, or anycombination thereof. In some embodiments in which the residue atposition 49 of the light chain according to the method of Kabat is notcysteine, the residue is serine. In some embodiments in which theresidue at position 57 of the heavy chain according to the method ofKabat is not cysteine, the residue is serine. In some embodiments inwhich the residue at position 36 of the light chain according to themethod of Kabat is not phenylalanine, the residue is tyrosine. In someembodiments in which the residue at position 46 of the light chainaccording to the method of Kabat is not arginine, the residue isleucine. In some embodiments in which the residue at position 71 of theheavy chain according to the method of Kabat is not arginine, theresidue is valine.

In some embodiments of the monoclonal antibody or antigen-bindingfragment that specifically binds human Tau, the antibody comprises: aheavy chain variable domain (HCVD) comprising SEQ ID NO: 268 and a lightchain variable domain (LCVD) comprising SEQ ID NO: 465; a HCVDcomprising SEQ ID NO: 268 and a LCVD comprising SEQ ID NO: 581; a HCVDcomprising SEQ ID NO: 384 and a LCVD comprising SEQ ID NO: 545; a HCVDcomprising SEQ ID NO: 393 and a LCVD comprising SEQ ID NO: 545; a HCVDcomprising SEQ ID NO: 402 and a LCVD comprising SEQ ID NO: 545; a HCVDcomprising SEQ ID NO: 384 and a LCVD comprising SEQ ID NO: 572; a HCVDcomprising SEQ ID NO: 393 and a LCVD comprising SEQ ID NO: 572; or aHCVD comprising SEQ ID NO: 402 and a LCVD comprising SEQ ID NO: 572.

In some embodiments of the monoclonal antibody or antigen-bindingfragment that specifically binds human Tau, the antibody is produced bythe cell line having ATCC deposit number PTA-124523 or ATCC depositnumber PTA-124524.

In some embodiments, the antibodies or antigen-binding fragmentsprovided herein bind monomeric wild-type human 2N4R Tau with a K_(D) ofless than about 0.5 nM as measured by surface plasmon resonance. In someembodiments, the antibodies or antigen-binding fragments bind human Tauat an epitope comprising the amino acid sequence HVPG (SEQ ID NO: 1133).Also provided are biepitopic antibodies or antigen-binding fragmentsthat bind human Tau at an epitope comprising the amino acid sequenceHVPG (SEQ ID NO: 1133) within repeat region 2 or repeat region 4. Incertain aspects, the antibodies or antigen-binding fragments bind humanTau at an epitope comprising the amino acid sequence HVPGG (SEQ ID NO:79). Also provided are biepitopic antibodies or antigen-bindingfragments that bind human Tau at an epitope comprising the amino acidsequence HVPGG (SEQ ID NO: 79) within repeat region 2 or repeat region4. In some embodiments, the monoclonal antibody or antigen-bindingfragment binds human Tau at the epitope comprising the amino acidsequence HVPGG (SEQ ID NO: 79) within repeat region 2 and/or repeatregion 4 with a binding preference that is at least about 10-foldgreater than binding at an epitope comprising the amino acid sequenceHKPGG (SEQ ID NO: 182) within repeat region 3 or at an epitopecomprising the amino acid sequence HQPGG (SEQ ID NO: 183) within repeatregion 1, as determined by a peptide binding assay. In some aspects, theantibodies or antigen-binding fragments provided herein do not bind Tauat an epitope comprising the amino acid sequence HVSGG (SEQ ID NO: 184)within repeat region 2 or at an epitope comprising the amino acidsequence HVLGG (SEQ ID NO: 185) within repeat region 2.

In some embodiments, the monoclonal antibodies or antigen-bindingfragments as provided herein are labeled.

Further provided are nucleic acid molecules encoding any of thedescribed monoclonal antibodies or antigen-binding fragments, vectorscomprising the nucleic acid molecules, cells that express the nucleicacid molecules, and methods of producing the anti-Tau antibodies orantigen-binding fragments by culturing such cells under conditionssuitable for production thereof. The methods of producing may furtherinvolve recovery of the antibody or antigen-binding fragment.

Also provided herein are pharmaceutical compositions of any of thedescribed monoclonal antibodies, or antigen-binding fragments thereof,that specifically bind a human Tau and a pharmaceutically acceptablecarrier.

Methods of use of the described monoclonal antibodies, orantigen-binding fragments thereof, that specifically bind a human Taualso are provided herein. In some embodiments, the antibodies orantigen-binding fragments that specifically bind a human Tau are for useas a medicament. In some aspects, the antibodies or antigen-bindingfragments that specifically bind a human Tau are for use in thetreatment of a Tauopathy or in the preparation of a medicament for thetreatment of a Tauopathy. Methods of treating a Tauopathy in a subjectalso are provided. In some embodiments, the methods of treating aTauopathy involve administering to the subject any of the describedmonoclonal antibodies, or antigen-binding fragments thereof, thatspecifically bind a human Tau under conditions effective to treat theTauopathy in the subject. In some aspects, the Tauopathy is Alzheimer'sdisease, frontotemporal dementia, or progressive supranuclear palsy. Thefrontotemporal dementia may be Pick's Disease, for example.

Further provided are methods for decreasing sarkosyl-insoluble Taulevels in a subject by administering to the subject any of the describedmonoclonal antibodies, or antigen-binding fragments thereof, thatspecifically bind a human Tau. Also provided are methods for inhibitingTau aggregation in a subject by administering to the subject any of thedescribed monoclonal antibodies, or antigen-binding fragments thereof,that specifically bind a human Tau. The methods may be performed invitro or in vivo.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the six isoforms of Tau expressed in adult humanbrain: 2N4R (UniProt Acc. No. P10636-8); 1N4R (UniProt Acc. No.P10636-7); 0N4R (UniProt Acc. No. P10636-6); 2N3R (UniProt Acc. No.P10636-5); 1N3R (UniProt Acc. No. P10636-4); and 0N3R (UniProt Acc. No.P10636-2) (Spillantini & Goedert, The Lancet, 2013, 12(6): 609-622).

FIG. 2 illustrates the region of protein (“Peptide antigen”) selected togenerate the anti-Tau antibodies described herein. FIG. 2 discloses SEQID NOS. 1137, 1138 and 1138, respectively, in order of appearance.

FIGS. 3A and 3B illustrate the results of the fine epitope mapping ofthe murine 7G6 (“ms7G6”) anti-Tau antibody. For FIG. 3A, translatedoverlapping peptides (SEQ ID NOs: 1-37, respectively) of the wild-type2N4R Tau sequence were synthesized and printed onto a glass chip alongwith a control HA-tag peptide. ms7G6 antibody binding (signal in figureinterior) and the control peptide (signal on figure periphery) wasdetected as described in the methods. FIG. 3B shows spot intensity as aresult of antibody binding to the peptide chip, quantified by the LI-COROdyssey™ and Pepslide™ Analyser software packages. Fluorescenceintensity was then plotted against peptide sequence to generate theepitope mapping data. FIG. 3B discloses SEQ ID NOS 1139-1140 and 1-37,respectively, in order of appearance.

FIG. 4 illustrates the results of the murine 7G6 antibody epitopesubstitution scanning of the peptide sequence KDNIKHVPGGGSVQI (SEQ IDNO: 26), corresponding to amino acids 294 to 308 of the human 2N4R Tauprotein. Each amino acid position of the peptide was replaced by everynaturally occurring amino acid possible, printed onto a glass chip, andprobed with the ms7G6 antibody. FIG. 4 illustrates the results forselect peptides (SEQ ID NOs 38-78, respectively). While ms7G6 antibodybinding allows some variation in the second position (valine) of SEQ IDNO: 79, antibody binding is completely dependent on the proline residueof SEQ ID NO: 79. No binding of antibody 7G6 to KDNIKHVSGGGSVQI (SEQ IDNO: 59) was observed. The latter is the sequence present in Tau P301Smutant protein.

FIGS. 5A and 5B illustrate the degree and rate of heparin-inducedaggregation for the wild-type and P301S Tau proteins, respectively, inthe presence and absence of ms7G6 (“7G6”) anti-Tau antibody. Mouse IgGthat is unable to bind Tau was included as a control antibody.

FIGS. 6A, 6B, 6C, and 6D illustrate the effects of vehicle control,human IgG1k, murine 7G6 anti-Tau antibody, and humanized7G6-HCzu25-LCzu18 antibody, respectively, in an in vitro cell-basedmodel of Tau seeding and aggregation.

FIG. 7 illustrates the results of pre-incubation of recombinant humanP301S Tau seeds with either vehicle, mouse IgG control antibody, andmurine anti-Tau antibodies 1F1, 7G6, or 8E5 in a preclinical in vivo Tauseeding model.

FIG. 8 illustrates the time course of insoluble Tau development in thehippocampus and cortex of P301S transgenic mice that were ICV-injectedwith recombinant P301S Tau seeds.

FIG. 9 illustrates the effect of peripheral, single repeat dosing ofms7G6 antibody in the P301S in vivo seeding model. ms7G6 caused areduction in insoluble Tau levels in hippocampus and cortex.

FIG. 10 illustrates the effect of peripheral multiple repeat dosing ofms7G6 antibody in the P301S in vivo seeding model. Reduction ofinsoluble Tau levels by antibody 7G6 was dose-dependent.

FIG. 11 illustrates the closest homologous human germline sequences tomurine anti-Tau antibody ms7G6. ms7G6 and homologous human germlinesequences were aligned. The Vh and VK domains are annotated by the IMGTand Kabat numbering systems. Identical residues are represented as a “.”in the human germline sequences. FIG. 11 discloses SEQ ID NOS 1141-1144,1143, 1145, 1143, 1146-1149, 1148, 1150 and 1148, respectively, in orderof appearance.

FIG. 12 compares the sequences of ms7G6 antibody heavy and light chainto humanized 7G6 Vh1 and Vk2 variants. The murine 7G6 and humanized 7G6variants were aligned. The Vh and Vk domains are annotated by the IMGTand Kabat numbering systems. Mutations are underlined. FIG. 12 disclosesSEQ ID NOS 1151-1174, respectively, in order of appearance.

FIGS. 13A, 13B, 13C, 13D, 13E, and 13F illustrate Tau binding by ELISAwith 7G6 LCzu1 humanized variants (FIG. 13A), 7G6 LCzu2 humanizedvariants (FIG. 13B), 7G6 LCzu3 humanized variants (FIG. 13C), 7G6 LCzu4humanized variants (FIG. 13D), 7G6 LCzu5 humanized variants (FIG. 13E),and 7G6 humanized variants with Ser substituted for Cys49 (according toKabat) on the light chain and Cys57 (according to Kabat) on the heavychain (FIG. 13F).

FIG. 14 illustrates the results of Tau binding by humanized 7G6 Vh1/Vk2variants analyzed by a direct ELISA. Samples were incubated for 1 h atroom temperature in 96-well plates coated with 2N4R Tau. Plates werewashed and then HRP-conjugated anti-mouse or anti-human antibodies wereadded to the wells. The amount of HRP activity in each well was measuredby QuantaBlu™ fluorescent substrate and the relative fluorescence units(RFUs) were detected by a SpectraMax M5 plate reader. The majority ofthe mAbs showed little difference in Tau binding in a direct ELISAassay. The notable exception was 7G6-LCzu9 which exhibited no binding,even at the highest concentrations. In addition, 7G6-LCzu22 showedreduced binding; Vκ Tyr36 in combination with Arg46 resulted indisruption of the antigen binding site.

FIG. 15 illustrates results of the SDS-PAGE analysis of heavy chain andlight chain stability for the Vh1 and Vκ2 humanized 7G6 variants. Twomicrograms of each mAb were mixed with 4× NuPAGE™ LDS Sample Buffer inthe absence of reducing agent and loaded onto a 4-12% Bis-Tris SDS-PAGEgel in MOPS buffer. Gels were stained with InstantBlue™ and destained inwater. HC-HC-LC trimers (HHL), HC-HC dimers (HH), and free LC (L) areindicated by arrows. The molecular weight of the markers is indicated inkDa.

FIG. 16 illustrates the BLAST alignment of antibody ms7G6 (“7G6”) to thehuman germline database at www_ncbi_nlm_nih_gov/igblast/. The Vh and Vkdomains are annotated by the IMGT and Kabat numbering systems. FIG. 16discloses SEQ ID NOS 1175-1178, 1177, 1179, 1180-1183, 1182 and 1184,respectively, in order of appearance.

FIG. 17 illustrates an alignment of ms7G6 and humanized 7G6 Vh3Nk1variants. The Vh and VK domains are annotated by the IMGT and Kabatnumbering systems. Mouse and humanized 7G6 variants were aligned. The Vhand VK domains are annotated by the IMGT and Kabat numbering systems.Mutations are underlined. FIG. 17 discloses SEQ ID NOS 1185-1207,respectively, in order of appearance.

FIG. 18 demonstrates direct binding of Tau by ms7G6 and humanized7G6Vh3/Vκ1 variants 7G6-HCzu11-LCzu11 (“HCzu11-LCzu11”),7G6-HCzu11-LCzu12 (“HCzu11-LCzu12”), 7G6-HCzu12-LCzu11(“HCzu12-LCzu11”), and 7G6-HCzu12-LCzu12 (“HCzu12-LCzu12”). Samples wereincubated for 1 h at room temperature in 96-well plates coated with 2N4Rwild-type recombinant Tau protein. After washing, HRP-conjugatedanti-mouse or anti-human antibodies were added to the wells. The amountof HRP activity in each well was measured by QuantaBlu™ fluorescentsubstrate and the RFUs were detected by a SpectraMax M5 plate reader.

FIGS. 19A and 19B demonstrate direct binding of Tau by ms7G6, non-Taubinding IgG1 control Ab mAb2, and humanized 7G6 Vh3/Vκ1 variants. FIG.19A demonstrates direct binding of Tau by ms7G6, non-Tau binding IgG1control Ab mAb2, and humanized 7G6 Vh3/Vκ1 variants 7G6-HCzu12-LCzu12(“HCzu12-LCzu12”), 7G6-HCzu13-LCzu12 (“HCzu13-LCzu12”),7G6-HCzu14-LCzu12 (“HCzu14-LCzu12”), 7G6-HCzu15-LCzu12(“HCzu15-LCzu12”), 7G6-HCzu16-LCzu12 (“HCzu16-LCzu12”),7G6-HCzu17-LCzu12 (“HCzu17-LCzu12”), 7G6-HCzu18-LCzu12(“HCzu18-LCzu12”), 7G6-HCzu19-LCzu12 (“HCzu19-LCzu12”), and7G6-HCzu20-LCzu12 (“HCzu20-LCzu12”). FIG. 19B demonstrates directbinding of Tau by ms7G6, non-Tau binding IgG1 control Ab mAb2, andhumanized 7G6 Vh3/Vκ1 variants 7G6-HCzu12-LCzu12 (“HCzu12-LCzu12”),7G6-HCzu12-LCzu13 (“HCzu12-LCzu13”), 7G6-HCzu12-LCzu14(“HCzu12-LCzu14”), 7G6-HCzu12-LCzu15 (“HCzu12-LCzu15”),7G6-HCzu12-LCzu16 (“HCzu12-LCzu16”), and 7G6-HCzu12-LCzu17(“HCzu12-LCzu17”). Samples were incubated for 1 hour at room temperaturein 96-well plates coated with 2N4R wild-type recombinant Tau protein.After the plates were washed, HRP-conjugated anti-mouse or anti-humandetection antibodies were added to the wells. The amount of HRP activityin each well was measured by QuantaBlu™ fluorescent substrate and theRFUs were detected by a SpectraMax M5 plate reader.

FIGS. 20A, 20B, and 20C illustrate the results of the non-reducingSDS-PAGE analysis of heavy chain/light chain stability for Vh3 and Vκ1variants of antibody 7G6.

FIG. 20A illustrates the results of the SDS-PAGE analysis of heavychain/light chain stability for Vh3 and Vκ1 variants 7G6-HCzu11-LCzu11(“HCzu11-LCzu11”), 7G6-HCzu11-LCzu12 (“HCzu11-LCzu12”),7G6-HCzu12-LCzu11 (“HCzu12-LCzu11”), and 7G6-HCzu12-LCzu12(“HCzu12-LCzu12”). FIG. 20B illustrates the results of the SDS-PAGEanalysis of heavy chain/light chain stability for Vh3 and Vκ1 variants7G6-HCzu12-LCzu12 (“HCzu12-LCzu12”), 7G6-HCzu13-LCzu12(“HCzu13-LCzu12”), 7G6-HCzu14-LCzu12 (“HCzu14-LCzu12”),7G6-HCzu16-LCzu12 (“HCzu16-LCzu12”), 7G6-HCzu17-LCzu12(“HCzu17-LCzu12”), and 7G6-HCzu18-LCzu12 (“HCzu18-LCzu12”). FIG. 20Cillustrates the results of the SDS-PAGE analysis of heavy chain/lightchain stability for Vh3 and Vκ1 variants 7G6-HCzu12-LCzu19(“HCzu12-LCzu19”), 7G6-HCzu12-LCzu13 (“HCzu12-LCzu13”),7G6-HCzu12-LCzu14 (“HCzu12-LCzu14”), 7G6-HCzu12-LCzu15(“HCzu12-LCzu15”), 7G6-HCzu12-LCzu16 (“HCzu12-LCzu16”), and7G6-HCzu12-LCzu17 (“HCzu12-LCzu17”). Two micrograms of each mAb weremixed with 4×NuPAGE™ LDS Sample Buffer in the absence of reducing agentand loaded onto a 4-12% Bis-Tris SDS-PAGE gel in MOPS buffer. Gels werestained with InstantBlue™ and destained in water. HC-LC dimers (HL) andfree HC are indicated by arrows. The molecular weight markers areindicated in kDa.

FIGS. 21A and 21B illustrate the results of SEC-HPLC analysis to assessthe homogeneity of antibody 7G6 humanized variants 7G6-HCzu8-LCzu6 (FIG.21A) and 7G6-HCzu25-LCzu18 (FIG. 21B) in solution. Five micrograms ofmAb 7G6 humanized variant were injected into an Agilent 1260 Infinitywith an AdvanceBio SEC 300A 2.7 um 4.6×50 Guard column, and AdvanceBioSEC 300A 2.7 um 4.6×300 mm column. Samples were analyzed in sodiumphosphate buffer, pH 6.5 at a flow rate of 0.35 mL/min, and theabsorbance at 280 nm was analyzed. Representative data for mAb7G6-HCzu8-LCzu6 or 7G6-HCzu25-LCzu18 are shown.

FIGS. 22A-L illustrate the thermal melting curves of F(ab′)2 fragmentsthat were analyzed by differential scanning calorimetry (DSC). FIGS.22A-L show the thermal melting curves for mAb1 (FIG. 22A), mAb2 (FIG.22B), chimeric (“xi”) 7G6 (“xi7G6”) (FIG. 22C), 7G6-HCzu8-LCzu6 (FIG.22D), 7G6-HCzu8-LCzu21 (FIG. 22E), 7G6-HCzu23-LCzu15 (FIG. 22F),7G6-HCzu24-LCzu15 (FIG. 22G), 7G6-HCzu25-LCzu15 (FIG. 22H),7G6-HCzu23-LCzu18 (FIG. 22I), 7G6-HCzu24-LCzu18 (FIG. 22J),7G6-HCzu25-LCzu18 (FIG. 22K), and 7G6-HCzu8-LCzu6 (FIG. 22L). F(ab′)2fragments and controls were subjected to thermal analysis ranging from25-100° C. using a scan rate of 100° C./hour. The profiles of thechimeric, 7G6-HCzu8 and 7G6-HCzu25 F(ab′)2 were similar tonon-Tau-binding IgG1 control mAb 1 and mAb2. 7G6-HCzu23 and 7G6-HCzu24,however, contained a second peak, indicating instability of the F(ab′)2fragment, possibly the dissociation of the HC-LC interaction. Thetransition midpoints of 7G6-HCzu8-LCzu21, 7G6-HCzu25-LCzu15, and7G6-HCzu25-LCzu18 were similar, ranging from 77.4 to 77.6° C. Themidpoint of 7G6-HCzu8-LCzu6 was one degree higher at 78.6° C.

FIGS. 23A and 23B show results of the immunoreactive T cell epitopeanalysis, providing putative hotspots (SEQ ID NOs: 80-94 in FIG. 23A;SEQ ID NOs: 95-111 in FIG. 23B) in humanized antibody 7G6 heavy chains.The peptides in the tables were identified as having identity 5% or lessidentity to human germline sequences. The percent homology of thepeptides to variable domain germline sequences was also taken intoconsideration. Peptides with ˜5% or less homology to variable regiongermline sequences and/or were predicted to bind three or more HLAalleles were identified as higher risk (highlighted in gray).

FIGS. 24A-24D show results of the immunoreactive T cell epitopeanalysis, providing putative hotspots in humanized antibody 7G6 lightchains (SEQ ID NOs: 112-130 in FIG. 24A; SEQ ID NOs: 131-150 in FIG.24B; SEQ ID NOs: 151-165 in FIG. 24C; and SEQ ID NOs: 166-180 in FIG.24D). The peptides in the tables were identified as having identity 5%or less identity to human germline sequences. The percent homology ofthe peptides to variable domain germline sequences was also taken intoconsideration. Peptides with ˜5% or less homology to variable regiongermline sequences and/or were predicted to bind three or more HLAalleles were identified as higher risk (highlighted in gray).

FIG. 25 shows images of immunohistochemical staining of AD, PSP, and PiDtissue samples with antibody 7G6-HCzu25-LCzu18. Antibody7G6-HCzu25-LCzu18 strongly and specifically recognizes pathological Tau(depicted by black arrows in each image) in human post-mortem diseasedbrain.

FIGS. 26A and 26B show the results of fine epitope mapping for humanizedantibodies 7G6-HCzu8/LCzu6 and 7G6-HCzu25/LCzu18, respectively.Fluorescent images of the chips and resulting intensity plots show thatthe 7G6-HCzu8/LCzu6 (FIG. 26A) and 7G6-HCzu25/LCzu18 (FIG. 26B)antibodies both bind to two major sites on the full length Tau protein.FIG. 26A discloses SEQ ID NOS 1-37, respectively, in order ofappearance. FIG. 26B discloses SEQ ID NOS 1-37, respectively, in orderof appearance.

FIG. 27 illustrates the degree and rate of heparin-induced aggregationfor the wild-type 2N4R Tau protein in the presence and absence ofantibody 7G6-HCzu25-LCzu18. Recombinant wild-type 2N4R Tau was inducedto aggregate under the conditions described in Example 15. Reactionscontained either no antibody (buffer only; open triangle), a human IgG1control antibody (solid diamond), or antibody 7G6-HCzu25-LCzu18 (opencircle). Thioflavin S (ThS) fluorescence was measured immediately afterheparin addition (day 0) and then on days 1, 2, 5 and 6 thereafter. Datais represented as mean±SD from four independent experiments. Statisticalanalysis (multiple t-tests comparing IgG control and antibody7G6-HCzu25-LCzu18) was performed for each time point (p≤0.01 **; p≤0.001***). FIG. 27 shows that 7G6-HCzu25-LCzu18 antibody effectively inhibitsTau aggregation in vitro. The effect was statistically significant whencomparing the IgG control and 7G6-HCzu25-LCzu18 antibody for days 1, 2,5 and 6 following incubation at 37° C. No significance was observed onday 0 just after the reactions were initiated following heparinaddition.

FIG. 28 illustrates the degree and rate of heparin-induced aggregationfor the wild-type 2N4R Tau protein in the presence and absence ofantibody 7G6 or antibody 7G6-HCzu25-LCzu18. Recombinant wild-type 2N4RTau was induced to aggregate under the conditions described in thematerials and methods. Reactions contained either no antibody (bufferonly; open triangle); a human IgG1 control antibody (solid diamond);antibody 7G6 (solid square); or antibody 7G6-HCzu25-LCzu18 (opencircle). Thioflavin S (ThS) fluorescence was measured immediately afterheparin addition (day 0) and then on days 1, 2, 5 and 6 thereafter. FIG.28 shows that, when both antibody 7G6 and antibody 7G6-HCzu25-LCzu18were tested according to the assay conditions provided in Example 5,both antibodies effectively inhibited Tau aggregation in vitro. The sameeffect size was seen between 7G6 and 7G6-HCzu25-LCzu18 antibodies.

FIG. 29 shows the normalized ThS positive rate in a K18 fibrilcell-based seeding assay after immunodepletion of samples with7G6-HCzu25-LCzu18 antibody. 1.5 and 15 μg/ml of 7G6-HCzu25-LCzu18antibody removed seeding effects of K18 fibril (>70% reduction vs humanIgG1 kappa control).

FIGS. 30A-30D illustrate the effect of antibody 7G6 on brainsarkosyl-insoluble Tau induced by intra-hippocampal Tau seed injectionin human P301S Tau transgenic mice. Tau seed or non-seed (100 mmol/Lsodium acetate, pH7.0) was stereotaxically injected into the lefthippocampus. 7G6 or control IgG at 40 mg/kg was intraperitonealyadministered once weekly for 3 weeks. Control IgG=Mouse IgG2b isotypecontrol antibody, 7G6=Anti-human Tau mouse IgG2b monoclonal antibodyData represent the mean±SEM (n=6 for Non-Seed, n=11 for Control IgG,7G6). **** P<0.0001, * P<0.05 versus control IgG (analyzed by 1-wayANOVA followed by Fisher's LSD test). The intraperitoneal administrationof 7G6 once weekly for 3 weeks at 40 mg/kg produced significantsuppression of the increase of sarkosyl-insoluble Tau in thecontralateral hippocampus induced by intra-hippocampal Tau seedinjection in P301S Tau transgenic mice.

FIGS. 31A and 31B show MTBR-Tau in cerebrospinal fluid from cynomolgusmonkey treated with 7G6-HCzu25-LCzu18 antibody. FIG. 31A shows boundMTBR-Tau. FIG. 31B shows free MTBR-Tau. Mean±SEM. Male Cynomolgus monkeyN=3 (Vehicle, 10 mg/kg, 30 mg/kg, 100 mg/kg).

FIG. 32 shows bound MTBR-Tau in human cerebrospinal fluid spiked with7G6-HCzu25-LCzu18 antibody (10, 100, 500, 1000 and 2000 ng/mL).

FIGS. 33A and 33B show the efficacy of Tau monomer or fibril uptake,respectively, in CHO cells overexpressing CD32A. 7G6-HCzu25-LCzu18antibody (3 μg/mL) significantly increased Tau monomer uptake comparedto human IgG1 control (3 μg/mL) (FIG. 33A). Likewise, 7G6-HCzu25-LCzu18antibody (0.3 and 3 μg/mL) also significantly increased Tau fibriluptake compared to human IgG1 control (3 μg/mL) (FIG. 33B). In bothcases, FcR inhibitor treatment significantly blocked the effect of7G6-HCzu25-LCzu18 antibody-induced Tau uptake in this cell assay system.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The following description characterizes antibodies, and antigen-bindingfragments thereof, that specifically bind to Tau. Also described arerelated polynucleotides capable of encoding these antibodies andantigen-binding fragments, cells expressing the antibodies andantigen-binding fragments, as well as associated vectors. In addition,methods of using the antibodies and antigen-binding fragments aredescribed. For example, the provided antibodies, and antigen-bindingfragments, may be used to treat a Tauopathy in a subject.

Various terms relating to aspects of the description are used throughoutthe specification and claims. Such terms are to be given their ordinarymeaning in the art unless otherwise indicated. Other specificallydefined terms are to be construed in a manner consistent with thedefinitions provided herein.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contentclearly dictates otherwise. Thus, for example, reference to “a cell”includes a combination of two or more cells, and the like.

The term “about” as used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, is meant toencompass variations of up to ±10% from the specified value, as suchvariations are appropriate to perform the disclosed methods. Unlessotherwise indicated, all numbers expressing quantities of ingredients,properties such as molecular weight, reaction conditions, and so forthused in the specification and claims are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth in thefollowing specification and attached claims are approximations that mayvary depending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

“Isolated” means a biological component (such as a nucleic acid, peptideor protein) has been substantially separated, produced apart from, orpurified away from other biological components of the organism in whichthe component naturally occurs, i.e., other chromosomal andextrachromosomal DNA and RNA, and proteins. Nucleic acids, peptides andproteins that have been “isolated” thus include nucleic acids andproteins purified by standard purification methods. “Isolated” nucleicacids, peptides and proteins that can be part of a composition and stillbe isolated if such composition is not part of the native environment ofthe nucleic acid, peptide, or protein. The term also embraces nucleicacids, peptides and proteins prepared by recombinant expression in ahost cell as well as chemically synthesized nucleic acids.

“Polynucleotide,” synonymously referred to as “nucleic acid molecule” or“nucleic acids,” refers to any polyribonucleotide orpolydeoxyribonucleotide, which may be unmodified RNA or DNA or modifiedRNA or DNA. “Polynucleotides” include, without limitation single- anddouble-stranded DNA, DNA that is a mixture of single- anddouble-stranded regions, single- and double-stranded RNA, and RNA thatis mixture of single- and double-stranded regions, hybrid moleculescomprising DNA and RNA that may be single-stranded or, more typically,double-stranded or a mixture of single- and double-stranded regions.“Polynucleotide” also embraces relatively short nucleic acid chains,often referred to as oligonucleotides.

The meaning of “substantially the same” can differ depending on thecontext in which the term is used. Because of the natural sequencevariation likely to exist among heavy and light chains and the genesencoding them, one would expect to find some level of variation withinthe amino acid sequences or the genes encoding the antibodies orantigen-binding fragments described herein, with little or no impact ontheir unique binding properties (e.g., specificity and affinity). Suchan expectation is due in part to the degeneracy of the genetic code, aswell as to the evolutionary success of conservative amino acid sequencevariations, which do not appreciably alter the nature of the encodedprotein. Accordingly, in the context of nucleic acid sequences,“substantially the same” means at least 65% identity between two or moresequences. Preferably, the term refers to at least 70% identity betweentwo or more sequences, more preferably at least 75% identity, morepreferably at least 80% identity, more preferably at least 85% identity,more preferably at least 90% identity, more preferably at least 91%identity, more preferably at least 92% identity, more preferably atleast 93% identity, more preferably at least 94% identity, morepreferably at least 95% identity, more preferably at least 96% identity,more preferably at least 97% identity, more preferably at least 98%identity, and more preferably at least 99% or greater identity. Suchidentity may be determined using nBLAST algorithm (Altschul et al.,(1990) Proc. Natl. Acad. Sci. USA 87:2264-8; Karlin and Altschul (1993)Proc. Natl. Acad. Sci. USA 90:5873-7).

The degree of variation that may occur within the amino acid sequence ofa protein without having a substantial effect on protein function ismuch lower than that of a nucleic acid sequence, since the samedegeneracy principles do not apply to amino acid sequences. Accordingly,in the context of an antibody or antigen-binding fragment,“substantially the same” means the sequences have “insubstantialdifferences”. Insubstantial differences are substitutions of 1, 2, 3, 4,5 or 6 amino acids in an antibody or antibody fragment amino acidsequence. Amino acid sequences substantially the same as the sequencesdisclosed herein are also part of this application. In some embodiments,the sequence identity can be about 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99% or higher. Other embodiments include Tau-specificantibodies, or antigen-binding fragments, that have framework, scaffold,or other non-binding regions that do not share significant identity withthe antibodies and antigen-binding fragments described herein, but doincorporate one or more CDRs or other sequences needed to confer bindingthat are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identicalto such sequences described herein.

A “vector” is a replicon, such as plasmid, phage, cosmid, or virus inwhich another nucleic acid segment may be operably inserted so as tobring about the replication or expression of the segment.

The terms “express” and “produce” are used synonymously herein, andrefer to the biosynthesis of a gene product. These terms encompass thetranscription of a gene into RNA. These terms also encompass translationof RNA into one or more polypeptides, and further encompass allnaturally occurring post-transcriptional and post-translationalmodifications. The expression or production of an antibody orantigen-binding fragment thereof may be within the cytoplasm of thecell, or into the extracellular milieu such as the growth medium of acell culture.

The term “treating” or “treatment” refers to any success or indicia ofsuccess in the attenuation or amelioration of an injury, pathology orcondition, including any objective or subjective parameter such asabatement, remission, diminishing of a symptom or making the conditionmore tolerable to the patient, slowing in the rate of degeneration ordecline, making the final point of degeneration less debilitating,improving a subject's physical or mental well-being, or prolonging thelength of survival. The treatment may be assessed by objective orsubjective parameters; including the results of a physical examination,neurological examination, or psychiatric evaluations. In a particularembodiment, the symptom of a Tauopathy is an impairment in cognition. Ina specific embodiment, the symptom of a Tauopathy is an impairment inlearning and/or memory. In a specific embodiment, the symptom of aTauopathy is a long-term memory loss. In a specific embodiment, thesymptom of a Tauopathy is dementia. In some embodiments, the symptom ofa Tauopathy is confusion, irritability, aggression, mood swings, or alanguage impairment. In some embodiments, the symptom of a Tauopathy isan impairment or loss of one or more cognitive functions such asreasoning, situational judgment, memory capacity, and/or learning.

The term “antibody” as used herein is meant in a broad sense andincludes immunoglobulin or antibody molecules including polyclonalantibodies, monoclonal antibodies including murine, human,human-adapted, humanized and chimeric monoclonal antibodies and antibodyfragments. In general, antibodies are proteins or peptide chains thatexhibit binding specificity to a specific antigen. Intact antibodies areheterotetrameric glycoproteins, composed of two identical light chainsand two identical heavy chains. Typically, each light chain is linked toa heavy chain by one covalent disulfide bond, while the number ofdisulfide linkages varies between the heavy chains of differentimmunoglobulin isotypes. Each heavy and light chain also has regularlyspaced intrachain disulfide bridges. Each heavy chain has at one end avariable domain (variable region) (VH) followed by a number of constantdomains (constant regions). Each light chain has a variable domain atone end (VL) and a constant domain at its other end; the constant domainof the light chain is aligned with the first constant domain of theheavy chain and the light chain variable domain is aligned with thevariable domain of the heavy chain. Antibody light chains of anyvertebrate species can be assigned to one of two clearly distinct types,namely kappa (κ) and lambda (λ), based on the amino acid sequences oftheir constant domains.

Immunoglobulins can be assigned to five major classes or isotypes,depending upon the type of constant domain possessed by its heavy chain,namely IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constantdomain amino acid sequence. IgA and IgG are further sub-classified asthe isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. The heavy chainconstant domains that correspond to the different classes ofimmunoglobulins are called a, 6, £, y, and 11, respectively.

An immunoglobulin light chain variable region or heavy chain variableregion consists of a “framework” region interrupted by three“antigen-binding sites”. The antigen-binding sites are defined usingvarious terms as follows: (i) the term Complementarity DeterminingRegions (CDRs) is based on sequence variability (Wu and Kabat, J. Exp.Med. 132:211-250, 1970). Generally, the antigen-binding site has sixCDRs; three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1,LCDR2, LCDR3) (Kabat et al., Sequences of Proteins of ImmunologicalInterest, 5th Ed. Public Health Service, National Institutes of Health,Bethesda, Md., 1991). The “IMGT-CDRs” as proposed by Lefranc (Lefranc etal., Dev. Comparat. Immunol. 27:55-77, 2003) are based on the comparisonof V domains from immunoglobulins and T-cell receptors. TheInternational ImMunoGeneTics (IMGT) database (www_imgt_org) provides astandardized numbering and definition of these regions. Thecorrespondence between CDRs and IMGT delineations is described inLefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003.

Antigen-binding fragments are any proteinaceous structure that mayexhibit binding affinity for a particular antigen. Some antigen-bindingfragments are composed of portions of intact antibodies that retainantigen-binding specificity of the parent antibody molecule. Forexample, antigen-binding fragments may comprise at least one variableregion (either a heavy chain or light chain variable region) or one ormore CDRs of an antibody known to bind a particular antigen. Examples ofsuitable antigen-binding fragments include, without limitation diabodiesand single-chain molecules as well as Fab, F(ab′)2, Fc, Fabc, and Fvmolecules, single chain (Sc) antibodies, individual antibody lightchains, individual antibody heavy chains, chimeric fusions betweenantibody chains or CDRs and other proteins, protein scaffolds, heavychain monomers or dimers, light chain monomers or dimers, dimersconsisting of one heavy and one light chain, and the like. All antibodyisotypes may be used to produce antigen-binding fragments. Additionally,antigen-binding fragments may include non-antibody proteinaceousframeworks that may successfully incorporate polypeptide segments in anorientation that confers affinity for a given antigen of interest, suchas protein scaffolds. Antigen-binding fragments may be recombinantlyproduced or produced by enzymatic or chemical cleavage of intactantibodies. The phrase “an antibody or antigen-binding fragment thereof”may be used to denote that a given antigen-binding fragment incorporatesone or more amino acid segments of the antibody referred to in thephrase.

“Specific binding” or “specifically binds” refers to the binding of anantibody or antigen-binding fragment to an antigen with greater affinitythan for other antigens. Typically, the antibody or antigen-bindingfragment binds to the antigen with an equilibrium dissociation constantK_(D) of about 5×10⁻⁸ M or less, for example about 5×10⁻⁹ M or less,about 1×10⁻⁹ M or less, about 1×10⁻¹⁰ M or less, or about 1×10⁻¹¹ M orless.

“Biepitopic” when used in the context of antibodies or antibodyfragments refers to the ability of the antibody or fragment tospecifically bind to two non-overlapping epitopes on the same targetantigen molecule though not necessarily simultaneously.

The term “subject” refers to human and non-human animals, including allvertebrates, e.g., mammals and non-mammals, such as non-human primates,mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians,and reptiles. In many embodiments of the described methods, the subjectis a human.

The embodiments described herein are not limited to particular methods,reagents, compounds, compositions or biological systems, which can, ofcourse, vary.

Described herein are isolated monoclonal antibodies and antigen-bindingfragments that specifically bind Tau, preferably human Tau (“anti-Tauantibodies”). Human Tau 2N4R (also referred to as Tau441) is set forthherein as SEQ ID NO: 181:

MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTDAGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLVDEGAPGKQAA AQPHTEIPEG TTAEEAGIGD TPSLEDEAAGHVTQARMVSK SKDGTGSDDK KAKGADGKTK IATPRGAAPPGQKGQANATR IPAKTPPAPK TPPSSGEPPK SGDRSGYSSPGSPGTPGSRS RTPSLPTPPT REPKKVAVVR TPPKSPSSAKSRLQTAPVPM PDLKNVKSKI GSTENLKHQP GGGKVQIINKKLDLSNVQSK CGSKDNIKHV PGGGSVQIVY KPVDLSKVTSKCGSLGNIHH KPGGGQVEVK SEKLDFKDRV QSKIGSLDNITHVPGGGNKK IETHKLTFRE NAKAKTDHGA EIVYKSPVVSGDTSPRHLSN VSSTGSIDMV DSPQLATLAD EVSASLAKQG L.

Human Tau also refers to Tau variants, for example, naturally occurringallelic variants, including those illustrated in FIG. 1 [2N4R (UniProtAcc. No. P10636-8); 1N4R (UniProt Acc. No. P10636-7); 0N4R (UniProt Acc.No. P10636-6); 2N3R (UniProt Acc. No. P10636-5); 1N3R (UniProt Acc. No.P10636-4); and 0N3R (UniProt Acc. No. P10636-2)], or sequencescontaining at least one amino acid substitution relative thereto. Insome embodiments, the antibodies or antigen-binding fragments are murineIgG, or derivatives thereof. While the anti-Tau antibodies orantigen-binding fragments may be human, humanized, or chimeric, theantibodies or antigen-binding fragments exemplified herein are murineand humanized antibodies.

In any of the embodiments described herein, the antibody thatspecifically binds Tau is preferably IgGl, more preferably human IgG1.The antibodies and antigen-binding fragments that specifically bind Tauas disclosed in the examples section are derived from mice. Similarantibodies may be derived from any species by recombinant means. Forexample, the antibodies or antigen-binding fragments may be chimericrat, goat, horse, swine, bovine, chicken, rabbit, camelid, donkey,human, and the like. For use in administration to humans, non-humanderived antibodies or antigen-binding fragments may be genetically orstructurally altered to be less antigenic upon administration to a humanpatient.

In some embodiments, the anti-Tau antibodies or antigen-bindingfragments are chimeric. As used herein, the term “chimeric” refers to anantibody, or antigen-binding fragment thereof, having at least someportion of at least one variable domain derived from the antibody aminoacid sequence of a non-human mammal, a rodent, or a reptile, while theremaining portions of the antibody, or antigen-binding fragment thereof,are derived from a human. For example, a chimeric antibody may comprisea mouse antigen binding domain with a human Fc or other such structuraldomain. Chimeric antibodies are renoted by the term “xi”. In someembodiments, the antibodies or antigen-binding fragments thatspecifically bind Tau are humanized antibodies or fragments. Humanizedantibodies may be chimeric immunoglobulins, immunoglobulin chains orfragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or otherantigen-binding subsequences of antibodies) that contain minimalsequence derived from non-human immunoglobulin. For the most part,humanized antibodies are human immunoglobulins (recipient antibody) inwhich residues from a complementary-determining region (CDR) of therecipient are replaced by residues from a CDR of a non-human species(donor antibody) such as mouse, rat or rabbit having the desiredspecificity, affinity, and capacity. In general, the humanized antibodywill comprise substantially all of at least one, and typically two,variable domains, in which all or substantially all of the CDR regionscorrespond to those of a non-human immunoglobulin and all orsubstantially all of the framework regions are those of a humanimmunoglobulin sequence. The humanized antibody may include at least aportion of an immunoglobulin constant region (Fc), typically that of ahuman immunoglobulin. Humanized antibody heavy or light chains aredenoted herein by the term “zu”.

The antibodies or antigen-binding fragments described herein can occurin a variety of forms, but will include one or more of the antibodyvariable domain segments or CDRs shown in Table 1.

TABLE 1Antibody segments of the described antibodies and antigen-binding fragments thereof 7G6 VH sequencesClone Name (Species Variable Domain Constant Domain & Heavy ChainHeavy Chain CDNA (DNA) (DNA) Isotype) DNA Sequence Amino Acid SequenceLeader (amino acid) (amino acid) mouse With leader [SEQ ID NO:With leader [SEQ ID ATGGGATG CAGGTCCAACTGCTGCAG GCCAAAACAACACCCCCA 7G6-190]: NO: 192] GAGCTGTA CCTGGGGCTGAGCTTGTG TCAGTCTATCCACTGGCC VhATGGGATGGAGCTGTATCATCCTCA MGWSCIILILVAAATGVHSQVQ TCATCCTCAAGCCTGGGGCTTCAGTA CCTGGGTGTGGAGATACA TTTTGGTAGCAGCAGCTACAGGTGTLLQPGAELVKPGASVIMSCKAS ATTTTGGT ATAATGTCCTGCAAGGCT ACTGGTTCCTCTGTGACTCCACTCCCAGGTCCAACTGCTGCAG GYTFTTYWITWVKQRPGQGLEW AGCAGCAGTCTGGCTACACCTTCACC CTGGGATGCCTGGTCAAG CCTGGGGCTGAGCTTGTGAAGCCTGIGDIYPGSSICNYNEKFKSKAT CTACAGGT ACCTACTGGATAACCTGG GGCTAGGGCTTCAGTAATAATGTCCTGCAA LTVDTSSSTAYMQLNSLTSEDS GTCCACTCGTGAAGCAGAGGCCTGGA (Nucleotides 415 GGCTTCTGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C CAAGGCCTTGAGTGGATT to 509 of SEQ IDTACTGGATAACCTGGGTGAAGCAGA LVTVSAAKTTPPSVYPLAPGCG (Nucleo-GGAGATATTTATCCTGGT NO: 190) GGCCTGGACAAGGCCTTGAGTGGAT DTTGSSVTLGCLVKGtides 1- AGTAGTATTTGTAACTAC [SEQ ID NO: 197] TGGAGATATTTATCCTGGTAGTAGTWithout leader [SEQ ID 57 of AATGAGAAGTTCAAGAGC AKTTPPSVYPLAPGCGDTATTTGTAACTACAATGAGAAGTTCA NO: 193]: SEQ ID AAGGCCACACTGACTGTATGSSVTLGCLVKG AGAGCAAGGCCACACTGACTGTAGA QVQLLQPGAELVKPGASVIMSC NO: 190)GACACATCCTCCAGCACA [SEQ ID NO: 198] CACATCCTCCAGCACAGCCTACATGKASGYTFTTYWITWVKQRPGQG [SEQ ID GCCTACATGCAGCTCAACCAGCTCAACAGCCTGACATCTGAGG LEWIGDIYPGSSICNYNEKFKS NO: 194]AGCCTGACATCTGAGGAC ACTCTGCGGTCTATTACTGTGCAAG KATLTVDTSSSTAYMQLNSLTSTCTGCGGTCTATTACTGT GGAGGATGGTTACGACGCCTGGTTT EDSAVYYCAREDGYDAWFAYWGGCAAGGGAGGATGGTTAC GCTTACTGGGGCCAAGGGACTCTGG QGTLVTVSAAKTTPPSVYPLAPGACGCCTGGTTTGCTTAC TCACTGTCTCCGCAGCCAAAACAAC GCGDTTGSSVTLGCLVKGTGGGGCCAAGGGACTCTG ACCCCCATCAGTCTATCCACTGGCC GTCACTGTCTCCGCACCTGGGTGTGGAGATACAACTGGTT (Nucleotides 58 to CCTCTGTGACTCTGGGATGCCTGGT414 of SEQ ID NO: CAAGGGCTA 190) Without leader [SEQ ID [SEQ ID NO: 195]NO: 191]: QVQLLQPGAELVKPGASV CAGGTCCAACTGCTGCAGCCTGGGGIMSCKASGYTFTTYWITW CTGAGCTTGTGAAGCCTGGGGCTTC VKQRPGQGLEWIGDIYPGAGTAATAATGTCCTGCAAGGCTTCT SSICNYNEKFKSKATLTV GGCTACACCTTCACCACCTACTGGADTSSSTAYMQLNSLTSED TAACCTGGGTGAAGCAGAGGCCTGG SAVYYCAREDGYDAWFAYACAAGGCCTTGAGTGGATTGGAGAT WGQGTLVTVSA ATTTATCCTGGTAGTAGTATTTGTA[SEQ ID NO: 196] ACTACAATGAGAAGTTCAAGAGCAA GGCCACACTGACTGTAGACACATCCTCCAGCACAGCCTACATGCAGCTCA ACAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTGCAAGGGAGGAT GGTTACGACGCCTGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGT CTCCGCAGCCAAAACAACACCCCCATCAGTCTATCCACTGGCCCCTGGGT GTGGAGATACAACTGGTTCCTCTGTGACTCTGGGATGCCTGGTCAAGGGC TA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG ATGGGCTGGTCCTGCATC GCATCCACCAAGGGCCCA HCzu1199]: NO: 201]: GTCCTGCA ATCCTGTTTCTGGTGGCC TCGGTCTTCCCCCTGGCAATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQ TCATCCTGACCGCCACCGGCGTGCAC CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AGCCAGGTGCAGCTGGTG TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGCAGTCTGGCGCCGAAGTG CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSICNYNEKFKSRVT CCACCGGC AAGAAACCTGGCGCCTCC GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTRDTSTSTVYMELSSLRSEDT GTGCACAGGTGAAGGTGTCCTGCAAG GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C GCTTCCGGCTACACCTTT TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-ACCACCTACTGGATCACC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tides 1 TGGGTGCGACAGGCTCCT GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGGACAGGGCCTGGAATGG GGACTCTACTCCCTCAGC ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID ATGGGCGACATCTACCCC AGCGTGGTGACCGTGCCCAGTCCCGCGTGACCATGACCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 199)GGCTCCTCCATCTGCAAC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGTGTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID TACAACGAGAAGTTCAAG CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 203]TCCCGCGTGACCATGACC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA CGGGACACCTCCACCAGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL ACCGTGTACATGGAACTGAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPTCCTCCCTGCGGAGCGAG TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP GACACCGCCGTGTACTAC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS TGCGCTAGAGAGGACGGCCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPVTACGACGCTTGGTTTGCC CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ TACTGGGGCCAGGGCACC CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL CTCGTGACCGTGTCATCTACCCTCATGATCTCCCGG ACGGTGTCGTGGAACTCAGGCGCCC SLSPGK (Nucleotides 58 toACCCCTGAGGTCACATGC TGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID414 of SEQ ID NO: GTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 202]:199) CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCG QVQLVQSGAEVKKPGASVKVSC[SEQ ID NO: 204] AAGTTCAACTGGTACGTG TGCCCTCCAGCAGCTTGGGCACCCAKASGYTFTTYWITWVRQAPGQG QVQLVQSGAEVKKPGASV GACGGCGTGGAGGTGCATGACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSICNYNEKFKS KVSCKASGYTFTTYWITWAATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACA RVTMTRDTSTSTVYMELSSLRSVRQAPGOGLEWMGDIYPG CGGGAGGAGCAGTACAAC AGAAAGTTGAGCCCAAATCTTGTGAEDTAVYYCAREDGYDAWFAYWG SSICNYNEKFKSRVTMTR AGCACGTACCGTGTGGTCCAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP DTSTSTVYMELSSLRSEDAGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGAC SSKSTSGGTAALGCLVKDYFPETAVYYCAREDGYDAWFAY CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL WGQGTLVTVSS GGCAAGGAGTACAAGTGCACCCAAGGACACCCTCATGATCTCC QSSGLYSLSSVVTVPSSSLGTQ [SEQ ID NO: 205]AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGG TYICNVNHKPSNTKVDKKVEPKCTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCC SCDKTHTCPPCPAPELLGGPSVAAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTG FLFPPKPKDTLMISRTPEVTCVAAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCA VVDVSHEDPEVKFNWYVDGVEVCCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTA HNAKTKPREEQYNSTYRVVSVLCCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGC TVLHQDWLNGKEYKCKVSNKALCTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACT PAPIEKTISKAKGQPREPQVYTAGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTG LPPSRDELTKNQVSLTCLVKGFAAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCA YPSDIAVEWESNGQPENNYKTTGACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCA PPVLDSDGSFFLYSKLTVDKSRGAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACC WQQGNVFSCSVMHEALHNHYTQGAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCC KSLSLSPGKACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGG TCCGACGGCTCCTTCTTCTCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACC CTTCTATCCCAGCGACATCGCCGTGGTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGG CAGCAGGGGAACGTCTTCAGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCAT CGTGCTGGACTCCGACGGCTCCTTCGAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGG TACACGCAGAAGAGCCTCACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGG CGTCTTCTCATGCTCCGTGATGCAT(Nucleotides 415 GAGGCTCTGCACAACCACTACACGC to 1401 of:: SEQ IDAGAAGAGCCTCTCCCTGTCTCCCGG NO: 199) GAAATGA [SEQ ID NO: 206]Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 200] SGGTAALGCLVKDYFPEPCAGGTGCAGCTGGTGCAGTCTGGCG VTVSWNSGALTSGVHTFP CCGAAGTGAAGAAACCTGGCGCCTCAVLQSSGLYSLSSVVTVP CGTGAAGGTGTCCTGCAAGGCTTCC SSSLGTQTYICNVNHKPSGGCTACACCTTTACCACCTACTGGA NTKVDKKVEPKSCDKTHT TCACCTGGGTGCGACAGGCTCCTGGCPPCPAPELLGGPSVFLF ACAGGGCCTGGAATGGATGGGCGAC PPKPKDTLMISRTPEVTCATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYV ACTACAACGAGAAGTTCAAGTCCCGDGVEVHNAKTKPREEQYN CGTGACCATGACCCGGGACACCTCC STYRVVSVLTVLHQDWLNACCAGCACCGTGTACATGGAACTGT GKEYKCKVSNKALPAPIE CCTCCCTGCGGAGCGAGGACACCGCKTISKAKGQPREPQVYTL CGTGTACTACTGCGCTAGAGAGGAC PPSRDELTKNQVSLTCLVGGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQP GGGGCCAGGGCACCCTCGTGACCGTENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCA LYSKLTVDKSRWQQGNVFTCGGTCTTCCCCCTGGCACCCTCCT SCS CCAAGAGCACCTCTGGGGGCACAGC [SEQ ID NO: 207]GGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGT TGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCAC CTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGA CGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGC ACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAA TGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG TACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCT GACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG GACTCCGACGGCTCCTTCTTCTTATATTCAAAGCTCACCGTGGACAAGAG CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTC TGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCCGGGAAATGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAG GCATCCACCAAGGGCCCA HCzu2208]: NO: 210]: GTCCTGCA TCTGGCGCCGAAGTGAAG TCGGTCTTCCCCCTGGCAATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQ TCATCCTGAAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSICNYNEKFKSRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTVDTSTSTVYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57)AACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI [SEQ ID CGCGTGACCATGACCGTG AGCGTGGTGACCGTGCCCAGTCCCGCGTGACCATGACCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 212]GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGTGTACATGKTHTCPPCPAPELLGGPSVFLF GTGTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD TCCCTGCGGAGCGAGGACGTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAG VSHEDPEVKFNWYVDGVEVHNAACCGCCGTGTACTACTGC AACACCAAGGTGGACAAG AGAGGACGGCTACGACGCTTGGTTTKTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTAC AAAGTTGAGCCCAAATCTGCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAP GACGCTTGGTTTGCCTACTGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAA IEKTISKAKGQPREPQVYTLPPTGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCA GGGCCCATCGGTCTTCCCCCTGGCASRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCT CCTGAACTCCTGGGGGGACCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV (Nucleotides 58 toCCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGT LDSDGSFFLYSKLTVDKSRWQQ414 of SEQ ID NO: CCCCCAAAACCCAAGGAC CAAGGACTACTTCCCCGAACCGGTGGNVFSCSVMHEALHNHYTQKSL 208) ACCCTCATGATCTCCCGG ACGGTGTCGTGGAACTCAGGCGCCCSLSPGK [SEQ ID NO: 213] ACCCCTGAGGTCACATGC TGACCAGCGGCGTGCACACCTTCCCWithout leader [SEQ ID QVQLVQSGAEVKKPGASV GTGGTGGTGGACGTGAGCGGCTGTCCTACAGTCCTCAGGACTC NO: 211]: KVSCKASGYTFTTYWITWCACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCG QVQLVQSGAEVKKPGASVKVSCVRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTG TGCCCTCCAGCAGCTTGGGCACCCAKASGYTFTTYWITWVRQAPGQG SSICNYNEKFKSRVTMTV GACGGCGTGGAGGTGCATGACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSICNYNEKFKS DTSTSTVYMELSSLRSEDAATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACA RVTMTVDTSTSTVYMELSSLRSTAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAAC AGAAAGTTGAGCCCAAATCTTGTGAEDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSS AGCACGTACCGTGTGGTCCAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP [SEQ ID NO: 214]AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGAC SSKSTSGGTAALGCLVKDYFPECACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAA PVTVSWNSGALTSGVHTFPAVLGGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCC QSSGLYSLSSVVTVPSSSLGTQAAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGG TYICNVNHKPSNTKVDKKVEPKCTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCC SCDKTHTCPPCPAPELLGGPSVAAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTG FLFPPKPKDTLMISRTPEVTCVAAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCA VVDVSHEDPEVKFNWYVDGVEVCCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTA HNAKTKPREEQYNSTYRVVSVLCCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGC TVLHQDWLNGKEYKCKVSNKALCTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACT PAPIEKTISKAKGQPREPQVYTAGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTG LPPSRDELTKNQVSLTCLVKGFAAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCA YPSDIAVEWESNGQPENNYKTTGACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCA PPVLDSDGSFFLYSKLTVDKSRGAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACC WQQGNVFSCSVMHEALHNHYTQGAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCC KSLSLSPGKACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGG TCCGACGGCTCCTTCTTCTCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACC CTTCTATCCCAGCGACATCGCCGTGGTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGG CAGCAGGGGAACGTCTTCAGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCAT CGTGCTGGACTCCGACGGCTCCTTCGAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGG TACACGCAGAAGAGCCTCACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGG CGTCTTCTCATGCTCCGTGATGCAT(Nucleotide 415 to GAGGCTCTGCACAACCACTACACGC 1401 of SEQ ID NO:AGAAGAGCCTCTCCCTGTCTCCCGG 208) [SEQ ID NO: GAAATGA 215]Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 209]: SGGTAALGCLVKDYFPEPCAGGTGCAGCTGGTGCAGTCTGGCG VTVSWNSGALTSGVHTFP CCGAAGTGAAGAAACCTGGCGCCTCAVLQSSGLYSLSSVVTVP CGTGAAGGTGTCCTGCAAGGCTTCC SSSLGTQTYICNVNHKPSGGCTACACCTTTACCACCTACTGGA NTKVDKKVEPKSCDKTHT TCACCTGGGTGCGACAGGCTCCTGGCPPCPAPELLGGPSVFLF ACAGGGCCTGGAATGGATGGGCGAC PPKPKDTLMISRTPEVTCATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYV ACTACAACGAGAAGTTCAAGTCCCGDGVEVHNAKTKPREEQYN CGTGACCATGACCGTGGACACCTCC STYRVVSVLTVLHQDWLNACCAGCACCGTGTACATGGAACTGT GKEYKCKVSNKALPAPIE CCTCCCTGCGGAGCGAGGACACCGCKTISKAKGQPREPQVYTL CGTGTACTACTGCGCTAGAGAGGAC PPSRDELTKNQVSLTCLVGGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQP GGGGCCAGGGCACCCTCGTGACCGTENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCA LYSKLTVDKSRWQQGNVFTCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSL CCAAGAGCACCTCTGGGGGCACAGCSLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC [SEQ ID NO: 216]TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAGGCATCCACCAAGGGCCCA HCzu3 217]: NO: 219]: GTCCTGCA TCTGGCGCCGAAGTGAAGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQTCATCCTG AAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSICNYNEKFKSRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTVDTSTSTAYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tide 1 to TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGCGTGACCATGACCGTG AGCGTGGTGACCGTGCCCAGTCCCGCGTGACCATGACCGTGGA CNVNHKPSNTKVDKKVEPKSCD O: 217)GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGCCTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID GCCTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 221]TCCCTGCGGAGCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 217) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 222] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID QVQLVQSGAEVKKPGASVGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 220]:KVSCKASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGQVQLVQSGAEVKKPGASVKVSC VRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA KASGYTFTTYWITWVRQAPGQG SSICNYNEKFKSRVTMTVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSICNYNEKFKSDTSTSTAYMELSSLRSED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARVTMTVDTSTSTAYMELSSLRS TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 223] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 217) GAAATGA[SEQ ID NO: 224] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 218]:SGGTAALGCLVKDYFPEP CAGGTGCAGCTGGTGCAGTCTGGCG VTVSWNSGALTSGVHTFPCCGAAGTGAAGAAACCTGGCGCCTC AVLQSSGLYSLSSVVTVP CGTGAAGGTGTCCTGCAAGGCTTCCSSSLGTQTYICNVNHKPS GGCTACACCTTTACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTGCGACAGGCTCCTGG CPPCPAPELLGGPSVFLF ACAGGGCCTGGAATGGATGGGCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYVACTACAACGAGAAGTTCAAGTCCCG DGVEVHNAKTKPREEQYN CGTGACCATGACCGTGGACACCTCCSTYRVVSVLTVLHQDWLN ACCAGCACCGCCTACATGGAACTGT GKEYKCKVSNKALPAPIECCTCCCTGCGGAGCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCTAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTCGTGACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 225] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGG GAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAGGCATCCACCAAGGGCCCA HCzu4 226]: NO: 228]: GTCCTGCA TCTGGCGCCGAAGTGAAGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQTCATCCTG AAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSICNYAQKFQGRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTVDTSTSTAYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tide 1 to TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS 57 ofGCCCAGAAATTCCAGGGC GGACTCTACTCCCTCAGC ATCTGCAACTACGCCCAGAAATTCCGLYSLSSVVTVPSSSLGTQTYI SEQ ID AGAGTGACCATGACCGTG AGCGTGGTGACCGTGCCCAGGGCAGAGTGACCATGACCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 226)GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGCCTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID GCCTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 230]TCCCTGCGGAGCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 226) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 231] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID QVQLVQSGAEVKKPGASVGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 229]:KVSCKASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGQVQLVQSGAEVKKPGASVKVSC VRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA KASGYTFTTYWITWVRQAPGQG SSICNYAQKFQGRVTMTVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSICNYAQKFQGDTSTSTAYMELSSLRSED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARVTMTVDTSTSTAYMELSSLRS TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 232] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401) AGAAGAGCCTCTCCCTGTCTCCCGG [SEQ ID NO: 233] GAAATGAASTKGPSVFPLAPSSKST Without leader [SEQ ID SGGTAALGCLVKDYFPEP NO: 227]:VTVSWNSGALTSGVHTFP CAGGTGCAGCTGGTGCAGTCTGGCG AVLQSSGLYSLSSVVTVPCCGAAGTGAAGAAACCTGGCGCCTC SSSLGTQTYICNVNHKPS CGTGAAGGTGTCCTGCAAGGCTTCCNTKVDKKVEPKSCDKTHT GGCTACACCTTTACCACCTACTGGA CPPCPAPELLGGPSVFLFTCACCTGGGTGCGACAGGCTCCTGG PPKPKDTLMISRTPEVTC ACAGGGCCTGGAATGGATGGGCGACVVVDVSHEDPEVKFNWYV ATCTACCCCGGCTCCTCCATCTGCA DGVEVHNAKTKPREEQYNACTACGCCCAGAAATTCCAGGGCAG STYRVVSVLTVLHQDWLN AGTGACCATGACCGTGGACACCTCCGKEYKCKVSNKALPAPIE ACCAGCACCGCCTACATGGAACTGT KTISKAKGQPREPQVYTLCCTCCCTGCGGAGCGAGGACACCGC PPSRDELTKNQVSLTCLV CGTGTACTACTGCGCTAGAGAGGACKGFYPSDIAVEWESNGQP GGCTACGACGCTTGGTTTGCCTACT ENNYKTTPPVLDSDGSFFGGGGCCAGGGCACCCTCGTGACCGT LYSKLTVDKSRWQQGNVF GTCATCTGCATCCACCAAGGGCCCASCSVMHEALHNHYTQKSL TCGGTCTTCCCCCTGGCACCCTCCT SLSPGKCCAAGAGCACCTCTGGGGGCACAGC [SEQ ID NO: 234] GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAGGCATCCACCAAGGGCCCA HCzu5 235]: NO: 237]: GTCCTGCA TCTGGCGCCGAAGTGAAGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQTCATCCTG AAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSISNYNEKFKSRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTVDTSTSTAYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTCCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTCCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGCGTGACCATGACCGTG AGCGTGGTGACCGTGCCCAGTCCCGCGTGACCATGACCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 235)GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGCCTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID GCCTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 239]TCCCTGCGGAGCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 235) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 240] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID QVQLVQSGAEVKKPGASVGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 238]:KVSCKASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGQVQLVQSGAEVKKPGASVKVSC VRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA KASGYTFTTYWITWVRQAPGQG SSISNYNEKFKSRVTMTVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSISNYNEKFKSDTSTSTAYMELSSLRSED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARVTMTVDTSTSTAYMELSSLRS TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 241] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 235) GAAATGA[SEQ ID NO: 242] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 236]:SGGTAALGCLVKDYFPEP CAGGTGCAGCTGGTGCAGTCTGGCG VTVSWNSGALTSGVHTFPCCGAAGTGAAGAAACCTGGCGCCTC AVLQSSGLYSLSSVVTVP CGTGAAGGTGTCCTGCAAGGCTTCCSSSLGTQTYICNVNHKPS GGCTACACCTTTACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTGCGACAGGCTCCTGG CPPCPAPELLGGPSVFLF ACAGGGCCTGGAATGGATGGGCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTCCA VVVDVSHEDPEVKFNWYVACTACAACGAGAAGTTCAAGTCCCG DGVEVHNAKTKPREEQYN CGTGACCATGACCGTGGACACCTCCSTYRVVSVLTVLHQDWLN ACCAGCACCGCCTACATGGAACTGT GKEYKCKVSNKALPAPIECCTCCCTGCGGAGCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCTAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTCGTGACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 243] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAGGCATCCACCAAGGGCCCA HCzu6 244]: NO: 246]: GTCCTGCA TCTGGCGCCGAAGTGAAGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQTCATCCTG AAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSISNYNEKFKSRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTVDTSTSTVYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTCCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTCCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGCGTGACCATGACCGTG AGCGTGGTGACCGTGCCCAGTCCCGCGTGACCATGACCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 244)GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGTGTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID GTGTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 248]TCCCTGCGGAGCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 244) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 249] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID QVQLVQSGAEVKKPGASVGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 247]:KVSCKASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGQVQLVQSGAEVKKPGASVKVSC VRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA KASGYTFTTYWITWVRQAPGQG SSISNYNEKFKSRVTMTVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSISNYNEKFKSDTSTSTVYMELSSLRSED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARVTMTVDTSTSTVYMELSSLRS TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 250] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401) AGAAGAGCCTCTCCCTGTCTCCCGG [SEQ ID NO: 251] GAAATGAASTKGPSVFPLAPSSKST Without leader [SEQ ID SGGTAALGCLVKDYFPEP NO: 245]:VTVSWNSGALTSGVHTFP CAGGTGCAGCTGGTGCAGTCTGGCG AVLQSSGLYSLSSVVTVPCCGAAGTGAAGAAACCTGGCGCCTC SSSLGTQTYICNVNHKPS CGTGAAGGTGTCCTGCAAGGCTTCCNTKVDKKVEPKSCDKTHT GGCTACACCTTTACCACCTACTGGA CPPCPAPELLGGPSVFLFTCACCTGGGTGCGACAGGCTCCTGG PPKPKDTLMISRTPEVTC ACAGGGCCTGGAATGGATGGGCGACVVVDVSHEDPEVKFNWYV ATCTACCCCGGCTCCTCCATCTCCA DGVEVHNAKTKPREEQYNACTACAACGAGAAGTTCAAGTCCCG STYRVVSVLTVLHQDWLN CGTGACCATGACCGTGGACACCTCCGKEYKCKVSNKALPAPIE ACCAGCACCGTGTACATGGAACTGT KTISKAKGQPREPQVYTLCCTCCCTGCGGAGCGAGGACACCGC PPSRDELTKNQVSLTCLV CGTGTACTACTGCGCTAGAGAGGACKGFYPSDIAVEWESNGQP GGCTACGACGCTTGGTTTGCCTACT ENNYKTTPPVLDSDGSFFGGGGCCAGGGCACCCTCGTGACCGT LYSKLTVDKSRWQQGNVF GTCATCTGCATCCACCAAGGGCCCASCSVMHEALHNHYTQKSL TCGGTCTTCCCCCTGGCACCCTCCT SLSPGKCCAAGAGCACCTCTGGGGGCACAGC [SEQ ID NO: 252] GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTG GACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTA CAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCA GCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACC ACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCC CGTGCTGGACTCCGACGGCTCCTTCTTCTTATATTCAAAGCTCACCGTGG ACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCAT GAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCCGG GAAATGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAG GCATCCACCAAGGGCCCA HCzu7253]: NO: 255]: GTCCTGCA TCTGGCGCCGAAGTGAAG TCGGTCTTCCCCCTGGCAATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQ TCATCCTGAAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSISNYAQKFQGRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTVDTSTSTVYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTCCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCCAGAAGTTCCAGGGC GGACTCTACTCCCTCAGC ATCTCCAACTACGCCCAGAAGTTCCGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGCGTGACCATGACCGTG AGCGTGGTGACCGTGCCCAGGGCCGCGTGACCATGACCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 253)GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGTGTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID GTGTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 257]TCCCTGCGGAGCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPVNucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 253) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 258] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID QVQLVQSGAEVKKPGASVGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 256]:KVSCKASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGQVQLVQSGAEVKKPGASVKVSC VRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA KASGYTFTTYWITWVRQAPGQG SSISNYAQKFQGRVTMTVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSISNYAQKFQGDTSTSTVYMELSSLRSED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARVTMTVDTSTSTVYMELSSLRS TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 259] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 253) GAAATGA[SEQ ID NO: 260] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 254]:SGGTAALGCLVKDYFPEP CAGGTGCAGCTGGTGCAGTCTGGCG VTVSWNSGALTSGVHTFPCCGAAGTGAAGAAACCTGGCGCCTC AVLQSSGLYSLSSVVTVP CGTGAAGGTGTCCTGCAAGGCTTCCSSSLGTQTYICNVNHKPS GGCTACACCTTTACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTGCGACAGGCTCCTGG CPPCPAPELLGGPSVFLF ACAGGGCCTGGAATGGATGGGCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTCCA VVVDVSHEDPEVKFNWYVACTACGCCCAGAAGTTCCAGGGCCG DGVEVHNAKTKPREEQYN CGTGACCATGACCGTGGACACCTCCSTYRVVSVLTVLHQDWLN ACCAGCACCGTGTACATGGAACTGT GKEYKCKVSNKALPAPIECCTCCCTGCGGAGCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCTAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTCGTGACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 261] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAGGCATCCACCAAGGGCCCA HCzu8 262]: NO: 264]: GTCCTGCA TCTGGCGCCGAAGTGAAGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQTCATCCTG AAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSISNYAQKFQGRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTRDTSTSTVYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTCCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCCAGAAGTTCCAGGGC GGACTCTACTCCCTCAGC ATCTCCAACTACGCCCAGAAGTTCCGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGCGTGACCATGACCCGG AGCGTGGTGACCGTGCCCAGGGCCGCGTGACCATGACCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 262)GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGTGTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID GTGTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 266]TCCCTGCGGAGCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 262) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 267] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID QVQLVQSGAEVKKPGASVGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 265]:KVSCKASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGQVQLVQSGAEVKKPGASVKVSC VRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA KASGYTFTTYWITWVRQAPGQG SSISNYAQKFQGRVTMTRGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSISNYAQKFQGDTSTSTVYMELSSLRSED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARVTMTRDTSTSTVYMELSSLRS TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 268] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 262) GAAATGA[SEQ ID NO: 269] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 263]:SGGTAALGCLVKDYFPEP CAGGTGCAGCTGGTGCAGTCTGGCG VTVSWNSGALTSGVHTFPCCGAAGTGAAGAAACCTGGCGCCTC AVLQSSGLYSLSSVVTVP CGTGAAGGTGTCCTGCAAGGCTTCCSSSLGTQTYICNVNHKPS GGCTACACCTTTACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTGCGACAGGCTCCTGG CPPCPAPELLGGPSVFLF ACAGGGCCTGGAATGGATGGGCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTCCA VVVDVSHEDPEVKFNWYVACTACGCCCAGAAGTTCCAGGGCCG DGVEVHNAKTKPREEQYN CGTGACCATGACCCGGGACACCTCCSTYRVVSVLTVLHQDWLN ACCAGCACCGTGTACATGGAACTGT GKEYKCKVSNKALPAPIECCTCCCTGCGGAGCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCTAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTCGTGACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 270] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAGGCATCCACCAAGGGCCCA HCzu9 271]: NO: 273]: GTCCTGCA TCTGGCGCCGAAGTGAAGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQTCATCCTG AAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSICNYAQKFQGRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTVDTSTSTVYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCCAGAAGTTCCAGGGC GGACTCTACTCCCTCAGC ATCTGCAACTACGCCCAGAAGTTCCGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGCGTGACCATGACCGTG AGCGTGGTGACCGTGCCCAGGGCCGCGTGACCATGACCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 271)GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGTGTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID GTGTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 275]TCCCTGCGGAGCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 271) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 276] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID QVQLVQSGAEVKKPGASVGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 274]:KVSCKASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGQVQLVQSGAEVKKPGASVKVSC VRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA KASGYTFTTYWITWVRQAPGQG SSICNYAQKFQGRVTMTVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSICNYAQKFQGDTSTSTVYMELSSLRSED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARVTMTVDTSTSTVYMELSSLRS TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 277] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 271) GAAATGA[SEQ ID NO: 278] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 272]:SGGTAALGCLVKDYFPEP CAGGTGCAGCTGGTGCAGTCTGGCG VTVSWNSGALTSGVHTFPCCGAAGTGAAGAAACCTGGCGCCTC AVLQSSGLYSLSSVVTVP CGTGAAGGTGTCCTGCAAGGCTTCCSSSLGTQTYICNVNHKPS GGCTACACCTTTACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTGCGACAGGCTCCTGG CPPCPAPELLGGPSVFLF ACAGGGCCTGGAATGGATGGGCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYVACTACGCCCAGAAGTTCCAGGGCCG DGVEVHNAKTKPREEQYN CGTGACCATGACCGTGGACACCTCCSTYRVVSVLTVLHQDWLN ACCAGCACCGTGTACATGGAACTGT GKEYKCKVSNKALPAPIECCTCCCTGCGGAGCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCTAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTCGTGACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 279] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG CAGGTGCAGCTGGTGCAGGCATCCACCAAGGGCCCA HCzu10 280]: NO: 282]: GTCCTGCA TCTGGCGCCGAAGTGAAGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSQVQTCATCCTG AAACCTGGCGCCTCCGTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLVQSGAEVKKPGASVKVSCKAS TTTCTGGT AAGGTGTCCTGCAAGGCT TCTGGGGGCACAGCGGCCGCACAGCCAGGTGCAGCTGGTGCAG GYTFTTYWITWVRQAPGQGLEW GGCCACCGTCCGGCTACACCTTTACC CTGGGCTGCCTGGTCAAG TCTGGCGCCGAAGTGAAGAAACCTGMGDIYPGSSICNYAQKFQGRVT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGCCTCCGTGAAGGTGTCCTGCAA MTRDTSTSTVYMELSSLRSEDT GTGCACAGGTGCGACAGGCTCCTGGA GTGACGGTGTCGTGGAAC GGCTTCCGGCTACACCTTTACCACCAVYYCAREDGYDAWFAYWGQGT C CAGGGCCTGGAATGGATG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTGCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCTGGACAGGGCCTGGAATGGATSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCAGGGCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCCAGAAGTTCCAGGGC GGACTCTACTCCCTCAGC ATCTGCAACTACGCCCAGAAGTTCCGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGCGTGACCATGACCCGG AGCGTGGTGACCGTGCCCAGGGCCGCGTGACCATGACCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 280)GACACCTCCACCAGCACC TCCAGCAGCTTGGGCACC CACCTCCACCAGCACCGTGTACATGKTHTCPPCPAPELLGGPSVFLF [SEQ ID GTGTACATGGAACTGTCC CAGACCTACATCTGCAACGAACTGTCCTCCCTGCGGAGCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 284]TCCCTGCGGAGCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCTAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCTAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTCG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TGACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTC TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTGACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 280) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 285] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID QVQLVQSGAEVKKPGASVGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 283]:KVSCKASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGQVQLVQSGAEVKKPGASVKVSC VRQAPGQGLEWMGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA KASGYTFTTYWITWVRQAPGQG SSICNYAQKFQGRVTMTRGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWMGDIYPGSSICNYAQKFQGDTSTSTVYMELSSLRSED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARVTMTRDTSTSTVYMELSSLRS TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 286] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 280) GAAATGA[SEQ ID NO: 287] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 281]:SGGTAALGCLVKDYFPEP CAGGTGCAGCTGGTGCAGTCTGGCG VTVSWNSGALTSGVHTFPCCGAAGTGAAGAAACCTGGCGCCTC AVLQSSGLYSLSSVVTVP CGTGAAGGTGTCCTGCAAGGCTTCCSSSLGTQTYICNVNHKPS GGCTACACCTTTACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTGCGACAGGCTCCTGG CPPCPAPELLGGPSVFLF ACAGGGCCTGGAATGGATGGGCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYVACTACGCCCAGAAGTTCCAGGGCCG DGVEVHNAKTKPREEQYN CGTGACCATGACCCGGGACACCTCCSTYRVVSVLTVLHQDWLN ACCAGCACCGTGTACATGGAACTGT GKEYKCKVSNKALPAPIECCTCCCTGCGGAGCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCTAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTCGTGACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 288] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu11 289]: NO: 291]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSICNYNEKFKSRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISRDNSKNTLYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAKEDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCAGTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCCGG AGCGTGGTGACCGTGCCCAGTCCCGGTTCACCATCTCCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 289)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCCTGTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID CTGTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGCGGGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 293]TCCCTGCGGGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGTGCCAAVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGT AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAAAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 289) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 294] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 292]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVSDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSICNYNEKFKSRFTISRGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVSDIYPGSSICNYNEKFKSDNSKNTLYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISRDNSKNTLYLQMNSLRA TAVYYCAKEDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAKEDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 295] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 289) GAAATGA[SEQ ID NO: 296] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 290]:SGGTAALGCLVKDYFPEP GAAGTGCAGCTGCTGGAATCTGGCG VTVSWNSGALTSGVHTFPGCGGACTGGTGCAGCCTGGCGGCTC AVLQSSGLYSLSSVVTVP TCTGAGACTGTCTTGTGCCGCCTCCSSSLGTQTYICNVNHKPS GGCTACACCTTCACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTCCGACAGGCTCCCGG CPPCPAPELLGGPSVFLF CAAGGGACTGGAATGGGTGTCCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYVACTACAACGAGAAGTTCAAGTCCCG DGVEVHNAKTKPREEQYN GTTCACCATCTCCCGGGACAACTCCSTYRVVSVLTVLHQDWLN AAGAACACCCTGTACCTCCAGATGA GKEYKCKVSNKALPAPIEACTCCCTGCGGGCCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGTGCCAAAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTGGTCACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 297] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu12 298]: NO: 300] GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVGDIYPGSSICNYNEKFKSRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISVDNSKSTAYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGAGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCACGGAGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCGTG AGCGTGGTGACCGTGCCCAGTCCCGGTTCACCATCTCCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 298)GACAACTCCAAGTCCACC TCCAGCAGCTTGGGCACC CAACTCCAAGTCCACCGCCTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID GCCTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 302]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 298) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 303] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 301]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSICNYNEKFKSRFTISVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVGDIYPGSSICNYNEKFKSDNSKSTAYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISVDNSKSTAYLQMNSLRA TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 304] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401) AGAAGAGCCTCTCCCTGTCTCCCGG [SEQ ID NO: 305] GAAATGAASTKGPSVFPLAPSSKST Without leader [SEQ ID SGGTAALGCLVKDYFPEP NO: 299]:VTVSWNSGALTSGVHTFP GAAGTGCAGCTGCTGGAATCTGGCG AVLQSSGLYSLSSVVTVPGCGGACTGGTGCAGCCTGGCGGCTC SSSLGTQTYICNVNHKPS TCTGAGACTGTCTTGTGCCGCCTCCNTKVDKKVEPKSCDKTHT GGCTACACCTTCACCACCTACTGGA CPPCPAPELLGGPSVFLFTCACCTGGGTCCGACAGGCTCCCGG PPKPKDTLMISRTPEVTC CAAGGGACTGGAATGGGTCGGAGACVVVDVSHEDPEVKFNWYV ATCTACCCCGGCTCCTCCATCTGCA DGVEVHNAKTKPREEQYNACTACAACGAGAAGTTCAAGTCCCG STYRVVSVLTVLHQDWLN GTTCACCATCTCCGTGGACAACTCCGKEYKCKVSNKALPAPIE AAGTCCACCGCCTACCTCCAGATGA KTISKAKGQPREPQVYTLACTCCCTGAGAGCCGAGGACACCGC PPSRDELTKNQVSLTCLV CGTGTACTACTGCGCCAGAGAGGACKGFYPSDIAVEWESNGQP GGCTACGACGCTTGGTTTGCTTACT ENNYKTTPPVLDSDGSFFGGGGCCAGGGCACCCTGGTCACCGT LYSKLTVDKSRWQQGNVF GTCATCTGCATCCACCAAGGGCCCASCSVMHEALHNHYTQKSL TCGGTCTTCCCCCTGGCACCCTCCT SLSPGKCCAAGAGCACCTCTGGGGGCACAGC [SEQ ID NO: 306] GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu13 307]: NO: 309]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVGDIYPGSSICNYADSVKGRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISVDNSKSTAYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGAGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCACGGAGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCGACTCCGTCAAGGGC GGACTCTACTCCCTCAGC ATCTGCAACTACGCCGACTCCGTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCGTG AGCGTGGTGACCGTGCCCAGGGCCGGTTCACCATCTCCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 307)GACAACTCCAAGTCCACC TCCAGCAGCTTGGGCACC CAACTCCAAGTCCACCGCCTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID GCCTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 311]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 307) [SEQ ID NO:ACCCTCATGATCTCCCGG ACGGTGTCGTGGAACTCAGGCGCCC SLSPGK 312]ACCCCTGAGGTCACATGC TGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ IDEVQLLESGGGLVQPGGSL GTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTCNO: 310]: RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTCTACTCCCTCAGCAGCGTGGTGACCG EVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVGDIYPGAAGTTCAACTGGTACGTG TGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKGSSICNYADSVKGRFTISV GACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCACLEWVGDIYPGSSICNYADSVKG DNSKSTAYLQMNSLRAED AATGCCAAGACAAAGCCGAAGCCCAGCAACACCAAGGTGGACA RFTISVDNSKSTAYLQMNSLRA TAVYYCAREDGYDAWFAYCGGGAGGAGCAGTACAAC AGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWGWGQGTLVTVSS AGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGCQGTLVTVSSASTKGPSVFPLAP [SEQ ID NO: 313] AGCGTCCTCACCGTCCTGCCAGCACCTGAACTCCTGGGGGGAC SSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAATCGTCAGTCTTCCTCTTCCCCCCAAA PVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGCACCCAAGGACACCCTCATGATCTCC QSSGLYSLSSVVTVPSSSIGTQ AAGGTCTCCAACAAAGCCCGGACCCCTGAGGTCACATGCGTGG TYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAGTGGTGGACGTGAGCCACGAAGACCC SCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCCTGAGGTCAAGTTCAACTGGTACGTG FLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAAGACGGCGTGGAGGTGCATAATGCCA VVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTGAGACAAAGCCGCGGGAGGAGCAGTA HNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAGCAACAGCACGTACCGTGTGGTCAGC TVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTCGTCCTCACCGTCCTGCACCAGGACT PAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTCGGCTGAATGGCAAGGAGTACAAGTG LPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGCCAAGGTCTCCAACAAAGCCCTCCCA YPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGGGCCCCCATCGAGAAAACCATCTCCA PPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCGAAGCCAAAGGGCAGCCCCGAGAACC WQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACCACAGGTGTACACCCTGCCCCCATCC KSLSLSPGK ACGCCTCCCGTGCTGGACCGGGATGAGCTGACCAAGAACCAGG TCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGGTTATATTCAAAGCTCACC CTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGGGAGTGGGAGAGCAATGGGCAGCCGG CAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCCTCATGCTCCGTGATGCAT CGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCACTTCTTATATTCAAAGCTCACCGTGG TACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAATCCCTGTCTCCCGGG CGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415GAGGCTCTGCACAACCACTACACGC to 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGGNO: 307) GAAATGA [SEQ ID NO: 314] Without leader [SEQ IDASTKGPSVFPLAPSSKST NO: 308]: SGGTAALGCLVKDYFPEPGAAGTGCAGCTGCTGGAATCTGGCG VTVSWNSGALTSGVHTFP GCGGACTGGTGCAGCCTGGCGGCTCAVLQSSGLYSLSSVVTVP TCTGAGACTGTCTTGTGCCGCCTCC SSSLGTQTYI CNVNHKPSGGCTACACCTTCACCACCTACTGGA NTKVDKKVEPKSCDKTHT TCACCTGGGTCCGACAGGCTCCCGGCPPCPAPELLGGPSVFLF CAAGGGACTGGAATGGGTCGGAGAC PPKPKDTLMISRTPEVTCATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYV ACTACGCCGACTCCGTCAAGGGCCGDGVEVHNAKTKPREEQYN GTTCACCATCTCCGTGGACAACTCC STYRVVSVLTVLHQDWLNAAGTCCACCGCCTACCTCCAGATGA GKEYKCKVSNKALPAPIE ACTCCCTGAGAGCCGAGGACACCGCKTISKAKGQPREPQVYTL CGTGTACTACTGCGCCAGAGAGGAC PPSRDELTKNQVSLTCLVGGCTACGACGCTTGGTTTGCTTACT KGFYPSDIAVEWESNGQP GGGGCCAGGGCACCCTGGTCACCGTENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCA LYSKLTVDKSRWQQGNVFTCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSL CCAAGAGCACCTCTGGGGGCACAGCSLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC [SEQ ID NO: 315]TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu14 316]: NO: 317]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVGDIYPGSSICNYADKFKGRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISVDNSKSTAYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGAGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCACGGAGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCGACAAGTTCAAGGGC GGACTCTACTCCCTCAGC ATCTGCAACTACGCCGACAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCGTG AGCGTGGTGACCGTGCCCAGGGCCGGTTCACCATCTCCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 316)GACAACTCCAAGTCCACC TCCAGCAGCTTGGGCACC CAACTCCAAGTCCACCGCCTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID GCCTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 319]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 316) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 320] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 318]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVGDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSICNYADKFKGRFTISVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVGDIYPGSSICNYADKFKGDNSKSTAYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISVDNSKSTAYLQMNSLRA TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 321] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 316) GAAATGA[SEQ ID NO: 322] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 1134]:SGGTAALGCLVKDYFPEP GAAGTGCAGCTGCTGGAATCTGGCG VTVSWNSGALTSGVHTFPGCGGACTGGTGCAGCCTGGCGGCTC AVLQSSGLYSLSSVVTVP TCTGAGACTGTCTTGTGCCGCCTCCSSSLGTQTYICNVNHKPS GGCTACACCTTCACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTCCGACAGGCTCCCGG CPPCPAPELLGGPSVFLF CAAGGGACTGGAATGGGTCGGAGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYVACTACGCCGACAAGTTCAAGGGCCG DGVEVHNAKTKPREEQYN GTTCACCATCTCCGTGGACAACTCCSTYRVVSVLTVLHQDWLN AAGTCCACCGCCTACCTCCAGATGA GKEYKCKVSNKALPAPIEACTCCCTGAGAGCCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCCAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCTTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTGGTCACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 323] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAATGGGCTGGTCCTGCATC HCzu15 324]: NO: 326]: GTCCTGCA TCTGGCGGCGGACTGGTGATCCTGTTTCTGGTGGCC ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG ACCGCCACCGGCGTGCAC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC AGCGAAGTGCAGCTGCTGGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC GAATCTGGCGGCGGACTG TCTGGCGGCGGACTGGTGCAGCCTGVGDIYPGSSICNYNEKFKSRFT CCACCGGC ACCTACTGGATCACCTGG GTGCAGCCTGGCGGCTCTGCGGCTCTCTGAGACTGTCTTGTGC ISVDNSKNTAYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC CTGAGACTGTCTTGTGCC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC GCCTCCGGCTACACCTTCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-GGAGACATCTACCCCGGC ACCACCTACTGGATCACC CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC TGGGTCCGACAGGCTCCCCGGAGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGCAAGGGACTGGAATGG ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCGTG GTCGGAGACATCTACCCCAGTCCCGGTTCACCATCTCCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 324)GACAACTCCAAGAACACC GGCTCCTCCATCTGCAAC CAACTCCAAGAACACCGCCTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID GCCTACCTCCAGATGAAC TACAACGAGAAGTTCAAGCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 328]TCCCTGAGAGCCGAGGAC TCCCGGTTCACCATCTCC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC GTGGACAACTCCAAGAACAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACACCGCCTACCTCCAGATG GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC AACTCCCTGAGAGCCGAG TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG GACACCGCCGTGTACTACGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTTGCGCCAGAGAGGACGGC CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to TACGACGCTTGGTTTGCT GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: TACTGGGGCCAGGGCACCCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 324) CTGGTCACCGTGTCATCTACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 329] GCATCCACCAAGGGCCCATGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLTCGGTCTTCCCCCTGGCA GGCTGTCCTACAGTCCTCAGGACTC NO: 327]:RLSCAASGYTFTTYWITW CCCTCCTCCAAGAGCACC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVGDIYPG TCTGGGGGCACAGCGGCCTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSICNYNEKFKSRFTISVCTGGGCTGCCTGGTCAAG GACCTACATCTGCAACGTGAATCAC LEWVGDIYPGSSICNYNEKFKSDNSKNTAYLQMNSLRAED GACTACTTCCCCGAACCG AAGCCCAGCAACACCAAGGTGGACARFTISVDNSKNTAYLQMNSLRA TAVYYCAREDGYDAWFAY GTGACGGTGTCGTGGAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSS [SEQTCAGGCGCCCTGACCAGC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAPID NO: 330] GGCGTGCACACCTTCCCG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE GCTGTCCTACAGTCCTCA CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGACTCTACTCCCTCAGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AGCGTGGTGACCGTGCCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK TCCAGCAGCTTGGGCACC TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV CAGACCTACATCTGCAAC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV GTGAATCACAAGCCCAGC GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV AACACCAAGGTGGACAAG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL AAAGTTGAGCCCAAATCT CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL TGTGACAAAACTCACACA GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT TGCCCACCGTGCCCAGCA GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF CCTGAACTCCTGGGGGGA CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT CCGTCAGTCTTCCTCTTC GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR CCCCCAAAACCCAAGGAC AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ ACCCTCATGATCTCCCGG ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACCCCTGAGGTCACATGC CGGGATGAGCTGACCAAGAACCAGGGTGGTGGTGGACGTGAGC TCAGCCTGACCTGCCTGGTCAAAGG CACGAAGACCCTGAGGTCCTTCTATCCCAGCGACATCGCCGTG AAGTTCAACTGGTACGTG GAGTGGGAGAGCAATGGGCAGCCGGGACGGCGTGGAGGTGCAT AGAACAACTACAAGACCACGCCTCC AATGCCAAGACAAAGCCGCGTGCTGGACTCCGACGGCTCCTTC CGGGAGGAGCAGTACAAC TTCTTATATTCAAAGCTCACCGTGGAGCACGTACCGTGTGGTC ACAAGAGCAGGTGGCAGCAGGGGAA AGCGTCCTCACCGTCCTGCGTCTTCTCATGCTCCGTGATGCAT CACCAGGACTGGCTGAAT GAGGCTCTGCACAACCACTACACGCGGCAAGGAGTACAAGTGC AGAAGAGCCTCTCCCTGTCTCCCGG AAGGTCTCCAACAAAGCC GAAATGACTCCCAGCCCCCATCGAG Without leader [SEQ ID AAAACCATCTCCAAAGCC NO: 325]:AAAGGGCAGCCCCGAGAA GAAGTGCAGCTGCTGGAATCTGGCG CCACAGGTGTACACCCTGGCGGACTGGTGCAGCCTGGCGGCTC CCCCCATCCCGGGATGAG TCTGAGACTGTCTTGTGCCGCCTCCCTGACCAAGAACCAGGTC GGCTACACCTTCACCACCTACTGGA AGCCTGACCTGCCTGGTCTCACCTGGGTCCGACAGGCTCCCGG AAAGGCTTCTATCCCAGC CAAGGGACTGGAATGGGTCGGAGACGACATCGCCGTGGAGTGG ATCTACCCCGGCTCCTCCATCTGCA GAGAGCAATGGGCAGCCGACTACAACGAGAAGTTCAAGTCCCG GAGAACAACTACAAGACC GTTCACCATCTCCGTGGACAACTCCACGCCTCCCGTGCTGGAC AAGAACACCGCCTACCTCCAGATGA TCCGACGGCTCCTTCTTCACTCCCTGAGAGCCGAGGACACCGC TTATATTCAAAGCTCACC CGTGTACTACTGCGCCAGAGAGGACGTGGACAAGAGCAGGTGG GGCTACGACGCTTGGTTTGCTTACT CAGCAGGGGAACGTCTTCGGGGCCAGGGCACCCTGGTCACCGT TCATGCTCCGTGATGCAT GTCATCTGCATCCACCAAGGGCCCAGAGGCTCTGCACAACCAC TCGGTCTTCCCCCTGGCACCCTCCT TACACGCAGAAGAGCCTCCCAAGAGCACCTCTGGGGGCACAGC TCCCTGTCTCCCGGG GGCCCTGGGCTGCCTGGTCAAGGAC(Nucleotides 415 TACTTCCCCGAACCGGTGACGGTGT to 1401 of SEQ IDCGTGGAACTCAGGCGCCCTGACCAG NO: 324) CGGCGTGCACACCTTCCCGGCTGTC[SEQ ID NO: 331] CTACAGTCCTCAGGACTCTACTCCC ASTKGPSVFPLAPSSKSTTCAGCAGCGTGGTGACCGTGCCCTC SGGTAALGCLVKDYFPEP CAGCAGCTTGGGCACCCAGACCTACVTVSWNSGALTSGVHTFP ATCTGCAACGTGAATCACAAGCCCA AVLQSSGLYSLSSVVTVPGCAACACCAAGGTGGACAAGAAAGT SSSLGTQTYICNVNHKPS TGAGCCCAAATCTTGTGACAAAACTNTKVDKKVEPKSCDKTHT CACACATGCCCACCGTGCCCAGCAC CPPCPAPELLGGPSVFLFCTGAACTCCTGGGGGGACCGTCAGT PPKPKDTLMISRTPEVTC CTTCCTCTTCCCCCCAAAACCCAAGVVVDVSHEDPEVKFNWYV GACACCCTCATGATCTCCCGGACCC DGVEVHNAKTKPREEQYNCTGAGGTCACATGCGTGGTGGTGGA STYRVVSVLTVLHQDWLN CGTGAGCCACGAAGACCCTGAGGTCGKEYKCKVSNKALPAPIE AAGTTCAACTGGTACGTGGACGGCG KTISKAKGQPREPQVYTLTGGAGGTGCATAATGCCAAGACAAA PPSRDELTKNQVSLTCLV GCCGCGGGAGGAGCAGTACAACAGCKGFYPSDIAVEWESNGQP ACGTACCGTGTGGTCAGCGTCCTCA ENNYKTTPPVLDSDGSFFCCGTCCTGCACCAGGACTGGCTGAA LYSKLTVDKSRWQQGNVF TGGCAAGGAGTACAAGTGCAAGGTCSCSVMHEALHNHYTQKSL TCCAACAAAGCCCTCCCAGCCCCCA SLSPGKTCGAGAAAACCATCTCCAAAGCCAA [SEQ ID NO: 332] AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu16 333]: NO: 335]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSICNYNEKFKSRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISVDNSKNTAYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCACTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCGTG AGCGTGGTGACCGTGCCCAGTCCCGGTTCACCATCTCCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 333)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCGCCTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID GCCTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 337]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 333) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 338] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 336]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVSDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSICNYNEKFKSRFTISVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVSDIYPGSSICNYNEKFKSDNSKNTAYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISVDNSKNTAYLQMNSLRA TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 339] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGAAACGTCTTCTCATGCTCCGTGATGCAT TGA GAGGCTCTGCACAACCACTACACGC (Nucleotides 415AGAAGAGCCTCTCCCTGTCTCCCGG to 1401 of SEQ ID GAAATGA NO: 333)Without leader [SEQ ID [SEQ ID NO: 340] NO: 334]: ASTKGPSVFPLAPSSKSTGAAGTGCAGCTGCTGGAATCTGGCG SGGTAALGCLVKDYFPEP GCGGACTGGTGCAGCCTGGCGGCTCVTVSWNSGALTSGVHTFP TCTGAGACTGTCTTGTGCCGCCTCC AVLQSSGLYSLSSVVTVPGGCTACACCTTCACCACCTACTGGA SSSLGTQTYICNVNHKPS TCACCTGGGTCCGACAGGCTCCCGGNTKVDKKVEPKSCDKTHT CAAGGGACTGGAATGGGTCTCCGAC CPPCPAPELLGGPSVFLFATCTACCCCGGCTCCTCCATCTGCA PPKPKDTLMISRTPEVTC ACTACAACGAGAAGTTCAAGTCCCGVVVDVSHEDPEVKFNWYV GTTCACCATCTCCGTGGACAACTCC DGVEVHNAKTKPREEQYNAAGAACACCGCCTACCTCCAGATGA STYRVVSVLTVLHQDWLN ACTCCCTGAGAGCCGAGGACACCGCGKEYKCKVSNKALPAPIE CGTGTACTACTGCGCCAGAGAGGAC KTISKAKGQPREPQVYTLGGCTACGACGCTTGGTTTGCTTACT PPSRDELTKNQVSLTCLV GGGGCCAGGGCACCCTGGTCACCGTKGFYPSDIAVEWESNGQP GTCATCTGCATCCACCAAGGGCCCA ENNYKTTPPVLDSDGSFFTCGGTCTTCCCCCTGGCACCCTCCT LYSKLTVDKSRWQQGNVF CCAAGAGCACCTCTGGGGGCACAGCSCSVMHEALHNHYTQKSL GGCCCTGGGCTGCCTGGTCAAGGAC SLSPGKTACTTCCCCGAACCGGTGACGGTGT [SEQ ID NO: 341] CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu17 342]: NO: 344]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSICNYNEKFKSRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISVDNSKNTLYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCACTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCGTG AGCGTGGTGACCGTGCCCAGTCCCGGTTCACCATCTCCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 342)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCCTGTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID CTGTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 346]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 342) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 347] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 345]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVSDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSICNYNEKFKSRFTISVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVSDIYPGSSICNYNEKFKSDNSKNTLYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISVDNSKNTLYLQMNSLRA TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 348] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 342) GAAATGA[SEQ ID NO: 349] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 343}:SGGTAALGCLVKDYFPEP GAAGTGCAGCTGCTGGAATCTGGCG VTVSWNSGALTSGVHTFPGCGGACTGGTGCAGCCTGGCGGCTC AVLQSSGLYSLSSVVTVP TCTGAGACTGTCTTGTGCCGCCTCCSSSLGTQTYICNVNHKPS GGCTACACCTTCACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTCCGACAGGCTCCCGG CPPCPAPELLGGPSVFLF CAAGGGACTGGAATGGGTCTCCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYVACTACAACGAGAAGTTCAAGTCCCG DGVEVHNAKTKPREEQYN GTTCACCATCTCCGTGGACAACTCCSTYRVVSVLTVLHQDWLN AAGAACACCCTGTACCTCCAGATGA GKEYKCKVSNKALPAPIEACTCCCTGAGAGCCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCCAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCTTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTGGTCACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 350] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu18 351]: NO: 353]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSICNYNEKFKSRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISRDNSKNTLYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCACTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTGCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCCGG AGCGTGGTGACCGTGCCCAGTCCCGGTTCACCATCTCCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 351)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCCTGTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID CTGTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 355]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 351) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 356] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 354] RLSCAASGYTFTTYWITWCACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCG EVQLLESGGGLVQPGGSLRLSCVRQAPGKGLEWVSDIYPG AAGTTCAACTGGTACGTG TGCCCTCCAGCAGCTTGGGCACCCAAASGYTFTTYWITWVRQAPGKG SSICNYNEKFKSRFTISR GACGGCGTGGAGGTGCATGACCTACATCTGCAACGTGAATCAC LEWVSDIYPGSSICNYNEKFKS DNSKNTLYLQMNSLRAEDAATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACA RFTISRDNSKNTLYLQMNSLRATAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAAC AGAAAGTTGAGCCCAAATCTTGTGAEDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSS AGCACGTACCGTGTGGTCCAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP [SEQ ID NO: 357]CACCAGGACTGGCTGAAT CCAGCACCTGAACTCCTGGGGGGAC SSKSTSGGTAALGCLVKDYFPEGGCAAGGAGTACAAGTGC CGTCAGTCTTCCTCTTCCCCCCAAA PVTVSWNSGALTSGVHTFPAVLAAGGTCTCCAACAAAGCC ACCCAAGGACACCCTCATGATCTCC QSSGLYSLSSVVTVPSSSLGTQCTCCCAGCCCCCATCGAG CGGACCCCTGAGGTCACATGCGTGG TYICNVNHKPSNTKVDKKVEPKAAAACCATCTCCAAAGCC TGGTGGACGTGAGCCACGAAGACCC SCDKTHTCPPCPAPELLGGPSVAAAGGGCAGCCCCGAGAA TGAGGTCAAGTTCAACTGGTACGTG FLFPPKPKDTLMISRTPEVTCVCCACAGGTGTACACCCTG GACGGCGTGGAGGTGCATAATGCCA VVDVSHEDPEVKFNWYVDGVEVCCCCCATCCCGGGATGAG AGACAAAGCCGCGGGAGGAGCAGTA HNAKTKPREEQYNSTYRVVSVLCTGACCAAGAACCAGGTC CAACAGCACGTACCGTGTGGTCAGC TVLHQDWLNGKEYKCKVSNKALAGCCTGACCTGCCTGGTC GTCCTCACCGTCCTGCACCAGGACT PAPIEKTISKAKGQPREPQVYTAAAGGCTTCTATCCCAGC GGCTGAATGGCAAGGAGTACAAGTG LPPSRDELTKNQVSLTCLVKGFGACATCGCCGTGGAGTGG CAAGGTCTCCAACAAAGCCCTCCCA YPSDIAVEWESNGQPENNYKTTGAGAGCAATGGGCAGCCG GCCCCCATCGAGAAAACCATCTCCA PPVLDSDGSFFLYSKLTVDKSRGAGAACAACTACAAGACC AAGCCAAAGGGCAGCCCCGAGAACC WQQGNVFSCSVMHEALHNHYTQACGCCTCCCGTGCTGGAC ACAGGTGTACACCCTGCCCCCATCC KSLSLSPGKTCCGACGGCTCCTTCTTC CGGGATGAGCTGACCAAGAACCAGG TTATATTCAAAGCTCACCTCAGCCTGACCTGCCTGGTCAAAGG GTGGACAAGAGCAGGTGG CTTCTATCCCAGCGACATCGCCGTGCAGCAGGGGAACGTCTTC GAGTGGGAGAGCAATGGGCAGCCGG TCATGCTCCGTGATGCATAGAACAACTACAAGACCACGCCTCC GAGGCTCTGCACAACCAC CGTGCTGGACTCCGACGGCTCCTTCTACACGCAGAAGAGCCTC TTCTTATATTCAAAGCTCACCGTGG TCCCTGTCTCCCGGGACAAGAGCAGGTGGCAGCAGGGGAA (Nucleotides 415 CGTCTTCTCATGCTCCGTGATGCATto 1401 of SEQ ID GAGGCTCTGCACAACCACTACACGC NO: 351)AGAAGAGCCTCTCCCTGTCTCCCGG [SEQ ID NO: 358] GAAATGA ASTKGPSVFPLAPSSKSTWithout leader [SEQ ID SGGTAALGCLVKDYFPEP NO: 352]: VTVSWNSGALTSGVHTFPGAAGTGCAGCTGCTGGAATCTGGCG AVLQSSGLYSLSSVVTVP GCGGACTGGTGCAGCCTGGCGGCTCSSSLGTQTYI CNVNHKPS TCTGAGACTGTCTTGTGCCGCCTCC NTKVDKKVEPKSCDKTHTGGCTACACCTTCACCACCTACTGGA CPPCPAPELLGGPSVFLF TCACCTGGGTCCGACAGGCTCCCGGPPKPKDTLMISRTPEVTC CAAGGGACTGGAATGGGTCTCCGAC VVVDVSHEDPEVKFNWYVATCTACCCCGGCTCCTCCATCTGCA DGVEVHNAKTKPREEQYN ACTACAACGAGAAGTTCAAGTCCCGSTYRVVSVLTVLHQDWLN GTTCACCATCTCCCGGGACAACTCC GKEYKCKVSNKALPAPIEAAGAACACCCTGTACCTCCAGATGA KTISKAKGQPREPQVYTL ACTCCCTGAGAGCCGAGGACACCGCPPSRDELTKNQVSLTCLV CGTGTACTACTGCGCCAGAGAGGAC KGFYPSDIAVEWESNGQPGGCTACGACGCTTGGTTTGCTTACT ENNYKTTPPVLDSDGSFF GGGGCCAGGGCACCCTGGTCACCGTLYSKLTVDKSRWQQGNVF GTCATCTGCATCCACCAAGGGCCCA SCSVMHEALHNHYTQKSLTCGGTCTTCCCCCTGGCACCCTCCT SLSPGK CCAAGAGCACCTCTGGGGGCACAGC[SEQ ID NO: 359] GGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGT TGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCAC CTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGA CGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGC ACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAA TGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG TACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCT GACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG GACTCCGACGGCTCCTTCTTCTTATATTCAAAGCTCACCGTGGACAAGAG CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTC TGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCCGGGAAATGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAA GCATCCACCAAGGGCCCAHCzu19 360]: NO: 362]: GTCCTGCA TCTGGCGGCGGACTGGTG TCGGTCTTCCCCCTGGCAATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQ TCATCCTGCAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSICNYADKFKGRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISRDNSKNTLYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCACTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCGACAAGTTCAAGGGC GGACTCTACTCCCTCAGC ATCTGCAACTACGCCGACAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCCGG AGCGTGGTGACCGTGCCCAGGGCCGGTTCACCATCTCCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 360)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCCTGTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID CTGTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 364]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 360) [SEQ ID NO:ACCCTCATGATCTCCCGG ACGGTGTCGTGGAACTCAGGCGCCC SLSPGK 365]ACCCCTGAGGTCACATGC TGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ IDEVQLLESGGGLVQPGGSL GTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTCNO: 363]: RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTCTACTCCCTCAGCAGCGTGGTGACCG EVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVSDIYPGAAGTTCAACTGGTACGTG TGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKGSSICNYADKFKGRFTISR GACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCACLEWVSDIYPGSSICNYADKFKG DNSKNTLYLQMNSLRAED AATGCCAAGACAAAGCCGAAGCCCAGCAACACCAAGGTGGACA RFTISRDNSKNTLYLQMNSLRA TAVYYCAREDGYDAWFAYCGGGAGGAGCAGTACAAC AGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWGWGQGTLVTVSS AGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGCQGTLVTVSSASTKGPSVFPLAP [SEQ ID NO: 366] AGCGTCCTCACCGTCCTGCCAGCACCTGAACTCCTGGGGGGAC SSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAATCGTCAGTCTTCCTCTTCCCCCCAAA PVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGCACCCAAGGACACCCTCATGATCTCC QSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCCCGGACCCCTGAGGTCACATGCGTGG TYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAGTGGTGGACGTGAGCCACGAAGACCC SCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCCTGAGGTCAAGTTCAACTGGTACGTG FLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAAGACGGCGTGGAGGTGCATAATGCCA VVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTGAGACAAAGCCGCGGGAGGAGCAGTA HNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAGCAACAGCACGTACCGTGTGGTCAGC TVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTCGTCCTCACCGTCCTGCACCAGGACT PAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTCGGCTGAATGGCAAGGAGTACAAGTG LPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGCCAAGGTCTCCAACAAAGCCCTCCCA YPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGGGCCCCCATCGAGAAAACCATCTCCA PPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCGAAGCCAAAGGGCAGCCCCGAGAACC WQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACCACAGGTGTACACCCTGCCCCCATCC KSLSLSPGK ACGCCTCCCGTGCTGGACCGGGATGAGCTGACCAAGAACCAGG TCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGGTTATATTCAAAGCTCACC CTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGGGAGTGGGAGAGCAATGGGCAGCCGG CAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCCTCATGCTCCGTGATGCAT CGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCACTTCTTATATTCAAAGCTCACCGTGG TACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAATCCCTGTCTCCCGGG CGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415GAGGCTCTGCACAACCACTACACGC to 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGGNO: 360) GAAATGA [SEQ ID NO: 367] Without leader [SEQ IDASTKGPSVFPLAPSSKST NO: 361]: SGGTAALGCLVKDYFPEPGAAGTGCAGCTGCTGGAATCTGGCG VTVSWNSGALTSGVHTFP GCGGACTGGTGCAGCCTGGCGGCTCAVLQSSGLYSLSSVVTVP TCTGAGACTGTCTTGTGCCGCCTCC SSSLGTQTYICNVNHKPSGGCTACACCTTCACCACCTACTGGA NTKVDKKVEPKSCDKTHT TCACCTGGGTCCGACAGGCTCCCGGCPPCPAPELLGGPSVFLF CAAGGGACTGGAATGGGTCTCCGAC PPKPKDTLMISRTPEVTCATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYV ACTACGCCGACAAGTTCAAGGGCCGDGVEVHNAKTKPREEQYN GTTCACCATCTCCCGGGACAACTCC STYRVVSVLTVLHQDWLNAAGAACACCCTGTACCTCCAGATGA GKEYKCKVSNKALPAPIE ACTCCCTGAGAGCCGAGGACACCGCKTISKAKGQPREPQVYTL CGTGTACTACTGCGCCAGAGAGGAC PPSRDELTKNQVSLTCLVGGCTACGACGCTTGGTTTGCTTACT KGFYPSDIAVEWESNGQP GGGGCCAGGGCACCCTGGTCACCGTENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCA LYSKLTVDKSRWQQGNVFTCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSL CCAAGAGCACCTCTGGGGGCACAGCSLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC [SEQ ID NO: 368]TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu20 369]: NO: 371]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSICNYADKFKGRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISRDNSKNTLYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAKEDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTGCAACTAC GCTGTCCTACAGTCCTCACTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCGACAAGTTCAAGGGC GGACTCTACTCCCTCAGC ATCTGCAACTACGCCGACAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCCGG AGCGTGGTGACCGTGCCCAGGGCCGGTTCACCATCTCCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 369)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCCTGTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID CTGTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 373]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAAVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAAAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 369) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 374] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 372]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVSDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSICNYADKFKGRFTISRGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVSDIYPGSSICNYADKFKGDNSKNTLYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISRDNSKNTLYLQMNSLRA TAVYYCAKEDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAKEDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 375] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotide 415 to GAGGCTCTGCACAACCACTACACGC1401 of SEQ ID NO: AGAAGAGCCTCTCCCTGTCTCCCGG 369) GAAATGA[SEQ ID NO: 376] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 370]SGGTAALGCLVKDYFPEP GAAGTGCAGCTGCTGGAATCTGGCG VTVSWNSGALTSGVHTFPGCGGACTGGTGCAGCCTGGCGGCTC AVLQSSGLYSLSSVVTVP TCTGAGACTGTCTTGTGCCGCCTCCSSSLGTQTYICNVNHKPS GGCTACACCTTCACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTCCGACAGGCTCCCGG CPPCPAPELLGGPSVFLF CAAGGGACTGGAATGGGTCTCCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTGCA VVVDVSHEDPEVKFNWYVACTACGCCGACAAGTTCAAGGGCCG DGVEVHNAKTKPREEQYN GTTCACCATCTCCCGGGACAACTCCSTYRVVSVLTVLHQDWLN AAGAACACCCTGTACCTCCAGATGA GKEYKCKVSNKALPAPIEACTCCCTGAGAGCCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCCAAAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCTTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTGGTCACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCATCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 377] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCCTCCACCAAGGGCCCA HCzu23 378]: NO: 380]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT  MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSISNYADSVKGRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISRDNSKNTLYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTCCAACTAC GCTGTCCTACAGTCCTCAGTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofGCCGACTCCGTCAAGGGC GGACTCTACTCCCTCAGC ATCTCCAACTACGCCGACTCCGTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCCGG AGCGTGGTGACCGTGCCCAGGGCCGGTTCACCATCTCCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 378)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCCTGTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID CTGTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGCGGGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 82]TCCCTGCGGGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCCTCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 378) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 383] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 381]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVSDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSISNYADSVKGRFTISRGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVSDIYPGSSISNYADSVKGDNSKNTLYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISRDNSKNTLYLQMNSLRA TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 384] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGCGTCTTCTCATGCTCCGTGATGCAT (Nucleotides 415 GAGGCTCTGCACAACCACTACACGCto 1401 of SEQ ID AGAAGAGCCTCTCCCTGTCTCCCGG NO: 378) GAAATGA[SEQ ID NO: 385] Without leader [SEQ ID ASTKGPSVFPLAPSSKST NO: 379]:SGGTAALGCLVKDYFPEP GAAGTGCAGCTGCTGGAATCTGGCG VTVSWNSGALTSGVHTFPGCGGACTGGTGCAGCCTGGCGGCTC AVLQSSGLYSLSSVVTVP TCTGAGACTGTCTTGTGCCGCCTCCSSSLGTQTYICNVNHKPS GGCTACACCTTCACCACCTACTGGA NTKVDKKVEPKSCDKTHTTCACCTGGGTCCGACAGGCTCCCGG CPPCPAPELLGGPSVFLF CAAGGGACTGGAATGGGTGTCCGACPPKPKDTLMISRTPEVTC ATCTACCCCGGCTCCTCCATCTCCA VVVDVSHEDPEVKFNWYVACTACGCCGACTCCGTCAAGGGCCG DGVEVHNAKTKPREEQYN GTTCACCATCTCCCGGGACAACTCCSTYRVVSVLTVLHQDWLN AAGAACACCCTGTACCTCCAGATGA GKEYKCKVSNKALPAPIEACTCCCTGCGGGCCGAGGACACCGC KTISKAKGQPREPQVYTL CGTGTACTACTGCGCCAGAGAGGACPPSRDELTKNQVSLTCLV GGCTACGACGCTTGGTTTGCCTACT KGFYPSDIAVEWESNGQPGGGGCCAGGGCACCCTGGTCACCGT ENNYKTTPPVLDSDGSFF GTCATCTGCCTCCACCAAGGGCCCALYSKLTVDKSRWQQGNVF TCGGTCTTCCCCCTGGCACCCTCCT SCSVMHEALHNHYTQKSLCCAAGAGCACCTCTGGGGGCACAGC SLSPGK GGCCCTGGGCTGCCTGGTCAAGGAC[SEQ ID NO: 386] TACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCCTCCACCAAGGGCCCA HCzu24 387]: NO: 389]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSISNYNEKFKSRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISRDNSKNTLYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTG TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTCCAACTAC GCTGTCCTACAGTCCTCAGTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTCCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCCGG AGCGTGGTGACCGTGCCCAGTCCCGGTTCACCATCTCCCGGGA CNVNHKPSNTKVDKKVEPKSCD NO: 387)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCCTGTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID CTGTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGCGGGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 391]TCCCTGCGGGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCCTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCCTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCCTCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 387) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 392] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 390]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVSDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSISNYNEKFKSRFTISRGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVSDIYPGSSISNYNEKFKSDNSKNTLYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISRDNSKNTLYLQMNSLRA TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 393] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGAAACGTCTTCTCATGCTCCGTGATGCAT TGA GAGGCTCTGCACAACCACTACACGC (Nucleotides 415AGAAGAGCCTCTCCCTGTCTCCCGG to 1401 of SEQ ID GAAATGA NO: 387)Without leader [SEQ ID [SEQ ID NO: 394] NO: 388]: ASTKGPSVFPLAPSSKSTGAAGTGCAGCTGCTGGAATCTGGCG SGGTAALGCLVKDYFPEP GCGGACTGGTGCAGCCTGGCGGCTCVTVSWNSGALTSGVHTFP TCTGAGACTGTCTTGTGCCGCCTCC AVLQSSGLYSLSSVVTVPGGCTACACCTTCACCACCTACTGGA SSSLGTQTYICNVNHKPS TCACCTGGGTCCGACAGGCTCCCGGNTKVDKKVEPKSCDKTHT CAAGGGACTGGAATGGGTGTCCGAC CPPCPAPELLGGPSVFLFATCTACCCCGGCTCCTCCATCTCCA PPKPKDTLMISRTPEVTC ACTACAACGAGAAGTTCAAGTCCCGVVVDVSHEDPEVKFNWYV GTTCACCATCTCCCGGGACAACTCC DGVEVHNAKTKPREEQYNAAGAACACCCTGTACCTCCAGATGA STYRVVSVLTVLHQDWLN ACTCCCTGCGGGCCGAGGACACCGCGKEYKCKVSNKALPAPIE CGTGTACTACTGCGCCAGAGAGGAC KTISKAKGQPREPQVYTLGGCTACGACGCTTGGTTTGCCTACT PPSRDELTKNQVSLTCLV GGGGCCAGGGCACCCTGGTCACCGTKGFYPSDIAVEWESNGQP GTCATCTGCCTCCACCAAGGGCCCA ENNYKTTPPVLDSDGSFFTCGGTCTTCCCCCTGGCACCCTCCT LYSKLTVDKSRWQQGNVF CCAAGAGCACCTCTGGGGGCACAGCSCSVMHEALHNHYTQKSL GGCCCTGGGCTGCCTGGTCAAGGAC SLSPGKTACTTCCCCGAACCGGTGACGGTGT [SEQ ID NO: 395] CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGGGAAATGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GAAGTGCAGCTGCTGGAAGCATCCACCAAGGGCCCA HCzu25 396]: NO: 398]: GTCCTGCA TCTGGCGGCGGACTGGTGTCGGTCTTCCCCCTGGCA ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSEVQTCATCCTG CAGCCTGGCGGCTCTCTG CCCTCCTCCAAGAGCACC TTCTGGTGGCCACCGCCACCGGCGTLLESGGGLVQPGGSLRLSCAAS TTTCTGGT AGACTGTCTTGTGCCGCC TCTGGGGGCACAGCGGCCGCACAGCGAAGTGCAGCTGCTGGAA GYTFTTYWITWVRQAPGKGLEW GGCCACCGTCCGGCTACACCTTCACC CTGGGCTGCCTGGTCAAG TCTGGCGGCGGACTGGTGCAGCCTGVSDIYPGSSISNYNEKFKSRFT CCACCGGC ACCTACTGGATCACCTGG GACTACTTCCCCGAACCGGCGGCTCTCTGAGACTGTCTTGTGC ISVDNSKNTLYLQMNSLRAEDT GTGCACAGGTCCGACAGGCTCCCGGC GTGACGGTGTCGTGGAAC CGCCTCCGGCTACACCTTCACCACCAVYYCAREDGYDAWFAYWGQGT C AAGGGACTGGAATGGGTC TCAGGCGCCCTGACCAGCTACTGGATCACCTGGGTCCGACAGG LVTVSSASTKGPSVFPLAPSSK (Nucleo-TCCGACATCTACCCCGGC GGCGTGCACACCTTCCCG CTCCCGGCAAGGGACTGGAATGGGTSTSGGTAALGCLVKDYFPEPVT tides 1 TCCTCCATCTCCAACTAC GCTGTCCTACAGTCCTCACTCCGACATCTACCCCGGCTCCTCC VSWNSGALTSGVHTFPAVLQSS to 57 ofAACGAGAAGTTCAAGTCC GGACTCTACTCCCTCAGC ATCTCCAACTACAACGAGAAGTTCAGLYSLSSVVTVPSSSLGTQTYI SEQ ID CGGTTCACCATCTCCGTG AGCGTGGTGACCGTGCCCAGTCCCGGTTCACCATCTCCGTGGA CNVNHKPSNTKVDKKVEPKSCD NO: 396)GACAACTCCAAGAACACC TCCAGCAGCTTGGGCACC CAACTCCAAGAACACCCTGTACCTCKTHTCPPCPAPELLGGPSVFLF [SEQ ID CTGTACCTCCAGATGAAC CAGACCTACATCTGCAACCAGATGAACTCCCTGAGAGCCGAGG PPKPKDTLMISRTPEVTCVVVD NO: 400]TCCCTGAGAGCCGAGGAC GTGAATCACAAGCCCAGC ACACCGCCGTGTACTACTGCGCCAGVSHEDPEVKFNWYVDGVEVHNA ACCGCCGTGTACTACTGC AACACCAAGGTGGACAAGAGAGGACGGCTACGACGCTTGGTTT KTKPREEQYNSTYRVVSVLTVL GCCAGAGAGGACGGCTACAAAGTTGAGCCCAAATCT GCTTACTGGGGCCAGGGCACCCTGG HQDWLNGKEYKCKVSNKALPAPGACGCTTGGTTTGCTTAC TGTGACAAAACTCACACA TCACCGTGTCATCTGCATCCACCAAIEKTISKAKGQPREPQVYTLPP TGGGGCCAGGGCACCCTG TGCCCACCGTGCCCAGCAGGGCCCATCGGTCTTCCCCCTGGCA SRDELTKNQVSLTCLVKGFYPS GTCACCGTGTCATCTCCTGAACTCCTGGGGGGA CCCTCCTCCAAGAGCACCTCTGGGG DIAVEWESNGQPENNYKTTPPV(Nucleotides 58 to CCGTCAGTCTTCCTCTTC GCACAGCGGCCCTGGGCTGCCTGGTLDSDGSFFLYSKLTVDKSRWQQ 414 of SEQ ID NO: CCCCCAAAACCCAAGGACCAAGGACTACTTCCCCGAACCGGTG GNVFSCSVMHEALHNHYTQKSL 396) ACCCTCATGATCTCCCGGACGGTGTCGTGGAACTCAGGCGCCC SLSPGK [SEQ ID NO: 401] ACCCCTGAGGTCACATGCTGACCAGCGGCGTGCACACCTTCCC Without leader [SEQ ID EVQLLESGGGLVQPGGSLGTGGTGGTGGACGTGAGC GGCTGTCCTACAGTCCTCAGGACTC NO: 399]:RLSCAASGYTFTTYWITW CACGAAGACCCTGAGGTC TACTCCCTCAGCAGCGTGGTGACCGEVQLLESGGGLVQPGGSLRLSC VRQAPGKGLEWVSDIYPG AAGTTCAACTGGTACGTGTGCCCTCCAGCAGCTTGGGCACCCA AASGYTFTTYWITWVRQAPGKG SSISNYNEKFKSRFTISVGACGGCGTGGAGGTGCAT GACCTACATCTGCAACGTGAATCAC LEWVSDIYPGSSISNYNEKFKSDNSKNTLYLQMNSLRAED AATGCCAAGACAAAGCCG AAGCCCAGCAACACCAAGGTGGACARFTISVDNSKNTLYLQMNSLRA TAVYYCAREDGYDAWFAY CGGGAGGAGCAGTACAACAGAAAGTTGAGCCCAAATCTTGTGA EDTAVYYCAREDGYDAWFAYWG WGQGTLVTVSSAGCACGTACCGTGTGGTC CAAAACTCACACATGCCCACCGTGC QGTLVTVSSASTKGPSVFPLAP[SEQ ID NO: 402] AGCGTCCTCACCGTCCTG CCAGCACCTGAACTCCTGGGGGGACSSKSTSGGTAALGCLVKDYFPE CACCAGGACTGGCTGAAT CGTCAGTCTTCCTCTTCCCCCCAAAPVTVSWNSGALTSGVHTFPAVL GGCAAGGAGTACAAGTGC ACCCAAGGACACCCTCATGATCTCCQSSGLYSLSSVVTVPSSSLGTQ AAGGTCTCCAACAAAGCC CGGACCCCTGAGGTCACATGCGTGGTYICNVNHKPSNTKVDKKVEPK CTCCCAGCCCCCATCGAG TGGTGGACGTGAGCCACGAAGACCCSCDKTHTCPPCPAPELLGGPSV AAAACCATCTCCAAAGCC TGAGGTCAAGTTCAACTGGTACGTGFLFPPKPKDTLMISRTPEVTCV AAAGGGCAGCCCCGAGAA GACGGCGTGGAGGTGCATAATGCCAVVDVSHEDPEVKFNWYVDGVEV CCACAGGTGTACACCCTG AGACAAAGCCGCGGGAGGAGCAGTAHNAKTKPREEQYNSTYRVVSVL CCCCCATCCCGGGATGAG CAACAGCACGTACCGTGTGGTCAGCTVLHQDWLNGKEYKCKVSNKAL CTGACCAAGAACCAGGTC GTCCTCACCGTCCTGCACCAGGACTPAPIEKTISKAKGQPREPQVYT AGCCTGACCTGCCTGGTC GGCTGAATGGCAAGGAGTACAAGTGLPPSRDELTKNQVSLTCLVKGF AAAGGCTTCTATCCCAGC CAAGGTCTCCAACAAAGCCCTCCCAYPSDIAVEWESNGQPENNYKTT GACATCGCCGTGGAGTGG GCCCCCATCGAGAAAACCATCTCCAPPVLDSDGSFFLYSKLTVDKSR GAGAGCAATGGGCAGCCG AAGCCAAAGGGCAGCCCCGAGAACCWQQGNVFSCSVMHEALHNHYTQ GAGAACAACTACAAGACC ACAGGTGTACACCCTGCCCCCATCCKSLSLSPGK ACGCCTCCCGTGCTGGAC CGGGATGAGCTGACCAAGAACCAGGTCCGACGGCTCCTTCTTC TCAGCCTGACCTGCCTGGTCAAAGG TTATATTCAAAGCTCACCCTTCTATCCCAGCGACATCGCCGTG GTGGACAAGAGCAGGTGG GAGTGGGAGAGCAATGGGCAGCCGGCAGCAGGGGAACGTCTTC AGAACAACTACAAGACCACGCCTCC TCATGCTCCGTGATGCATCGTGCTGGACTCCGACGGCTCCTTC GAGGCTCTGCACAACCAC TTCTTATATTCAAAGCTCACCGTGGTACACGCAGAAGAGCCTC ACAAGAGCAGGTGGCAGCAGGGGAA TCCCTGTCTCCCGGGAAACGTCTTCTCATGCTCCGTGATGCAT TGA GAGGCTCTGCACAACCACTACACGC (Nucleotides 415AGAAGAGCCTCTCCCTGTCTCCCGG to 1401 of SEQ ID GAAATGA NO: 396) [SEQ IDWithout leader [SEQ ID NO: 403] NO: 397]: ASTKGPSVFPLAPSSKSTGAAGTGCAGCTGCTGGAATCTGGCG SGGTAALGCLVKDYFPEP GCGGACTGGTGCAGCCTGGCGGCTCVTVSWNSGALTSGVHTFP TCTGAGACTGTCTTGTGCCGCCTCC AVLQSSGLYSLSSVVTVPGGCTACACCTTCACCACCTACTGGA SSSLGTQTYICNVNHKPS TCACCTGGGTCCGACAGGCTCCCGGNTKVDKKVEPKSCDKTHT CAAGGGACTGGAATGGGTCTCCGAC CPPCPAPELLGGPSVFLFATCTACCCCGGCTCCTCCATCTCCA PPKPKDTLMISRTPEVTC ACTACAACGAGAAGTTCAAGTCCCGVVVDVSHEDPEVKFNWYV GTTCACCATCTCCGTGGACAACTCC DGVEVHNAKTKPREEQYNAAGAACACCCTGTACCTCCAGATGA STYRVVSVLTVLHQDWLN ACTCCCTGAGAGCCGAGGACACCGCGKEYKCKVSNKALPAPIE CGTGTACTACTGCGCCAGAGAGGAC KTISKAKGQPREPQVYTLGGCTACGACGCTTGGTTTGCTTACT PPSRDELTKNQVSLTCLV GGGGCCAGGGCACCCTGGTCACCGTKGFYPSDIAVEWESNGQP GTCATCTGCATCCACCAAGGGCCCA ENNYKTTPPVLDSDGSFFTCGGTCTTCCCCCTGGCACCCTCCT LYSKLTVDKSRWQQGNVF CCAAGAGCACCTCTGGGGGCACAGCSCSVMHEALHNHYTQKSL GGCCCTGGGCTGCCTGGTCAAGGAC SLSPGKTACTTCCCCGAACCGGTGACGGTGT [SEQ ID NO: 404] CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTC CAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCTTAT ATTCAAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCCGG GAAATGA 7G6 VL sequencesClone Name (Species CDNA Variable Domain Constant Domain & Light ChainLight Chain Position (cDNA) (cDNA) Isotype) DNA SequenceAmino Acid Sequence Leader (amino acid) (amino acid) mouseWith leader [SEQ ID NO: With leader [SEQ ID ATGAAGTT GATGTTTTGATGACCCAACGGGCTGATGCTGCACCA 7G6- 405]: NO: 407]: GCCTGTTA ACTCCACTCTCCCTGCCTACTGTATCCATCTTCCCA V_(K) ATGAAGTTGCCTGTTAGGCTGTTGGMKLPVRLLVMMFWIPASSSDVL GGCTGTTG GTCAGTCTTGGAGATCAA CCTTCTGATGATGTTCTGGATTCCTGCTTC MTQTPLSLPVSLGDQASISCRS GTGATGATGCCTCCATCTCTTGCAGA (nucleotides 394 CAGCAGTGATGTTTTGATGACCCAASQSILHSNGNTYLEWYLQKPGQ GTTCTGGA TCTAGTCAGAGCATTTTA to 434 of SEQ IDACTCCACTCTCCCTGCCTGTCAGTC SPKLLICKVSNRFSGVPDRFSG TTCCTGCTCATAGTAATGGAAACACC NO: 405) TTGGAGATCAAGCCTCCATCTCTTGSGSGTDFTLKISRVEAEDLGVY TCCAGCAG TATTTAGAATGGTACCTG [SEQ ID NO: 412]CAGATCTAGTCAGAGCATTTTACAT YCFQGSHVPFTFGSGTKLEIKR T CAGAAACCAGGCCAGTCTKRADAAPTVSIFPPS AGTAATGGAAACACCTATTTAGAAT ADAAPTVSIFPPS (nucleo-CCAAAGCTCCTGATTTGC [SEQ ID NO: 413] GGTACCTGCAGAAACCAGGCCAGTCWithout leader [SEQ ID tides 1 AAAGTTTCCAACCGATTTTCCAAAGCTCCTGATTTGCAAAGTT O: 408]: to 57 of TCTGGGGTCCCAGACAGGTCCAACCGATTTTCTGGGGTCCCAG DVLMTQTPLSLPVSLGDQASIS SEQ IDTTCAGTGGCAGTGGATCA ACAGGTTCAGTGGCAGTGGATCAGG CRSSQSILHSNGNTYLEWYLQKNO: 405) GGGACAGATTTCACACTC GACAGATTTCACACTCAAGATCAGCPGQSPKLLICKVSNRFSGVPDR [SEQ ID AAGATCAGCAGAGTGGAGAGAGTGGAGGCTGAGGATCTGGGAG FSGSGSGTDFTLKISRVEAEDL NO: 409]GCTGAGGATCTGGGAGTT TTTATTACTGCTTTCAAGGTTCACA GVYYCFQGSHVPFTFGSGTKLETATTACTGCTTTCAAGGT TGTTCCATTCACGTTCGGCTCGGGG IKRADAAPTVSIFPPSTCACATGTTCCATTCACG ACAAAGTTGGAAATAAAACGGGCTG TTCGGCTCGGGGACAAAGATGCTGCACCAACTGTATCCATCTT TTGGAAATAAAA CCCACCTTC (nucleotides 58 toWithout leader [SEQ ID 393 of SEQ ID NO: NO: 406]: 405)GATGTTTTGATGACCCAAACTCCAC [SEQ ID NO: 410] TCTCCCTGCCTGTCAGTCTTGGAGADVLMTQTPLSLPVSLGDQ TCAAGCCTCCATCTCTTGCAGATCT ASISCRSSQSILHSNGNTAGTCAGAGCATTTTACATAGTAATG YLEWYLQKPGQSPKLLIC GAAACACCTATTTAGAATGGTACCTKVSNRFSGVPDRFSGSGS GCAGAAACCAGGCCAGTCTCCAAAG GTDFTLKISRVEAEDLGVCTCCTGATTTGCAAAGTTTCCAACC YYCFQGSHVPFTFGSGTK GATTTTCTGGGGTCCCAGACAGGTTLEIK CAGTGGCAGTGGATCAGGGACAGAT [SEQ ID NO: 411]TTCACACTCAAGATCAGCAGAGTGG AGGCTGAGGATCTGGGAGTTTATTACTGCTTTCAAGGTTCACATGTTCCA TTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAACGGGCTGATGCTGC ACCAACTGTATCCATCTTCCCACCT TC 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAGCGAACTGTGGCTGCACCA LCzu1 414]: NO: 416]: GTCCTGCA TCCCCCCTGTCCCTGCCTTCTGTCTTCATCTTCCCG ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVVTCATCCTG GTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSILHSNGNTYLEWFQQRPGQ GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRRLIYKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTTCCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCT GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCAGACGGCTGATCTAC TCGGGTAACTCCCAGGAG GGTTCCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tide 1 to AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACTCCCAGACGGCTGATCTACAAGGTG ALQSGNSQESVTEQDSKDSTYS 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 414) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 417]: NO: 418] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWFQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRRLIYKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotide 394 to CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotide 58 to 714 of SEQ ID NO: TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: 414) TGCTGAATAACTTCTATCCCAGAGAGTASVVCLLNNFYPREAKVQWK 414) [SEQ ID NO: 421] GGCCAAAGTACAGTGGAAGGTGGATVDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 419] RTVAAPSVFIFPPSDEQLAACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYA DVVMTQSPLSLPVTLGQPKSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAG CEVTHQGLSSPVTKSFNRGECASISCRSSQSILHSNGNT AKVQWKVDNALQSGNSQE CAAGGACAGCACCTACAGCCTCAGCYLEWFQQRPGQSPRRLIY SVTEQDSKDSTYSLSSTL AGCACCCTGACGCTGAGCAAAGCAGKVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVT ACTACGAGAAACACAAAGTCTACGCGTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGEC CTGCGAAGTCACCCATCAGGGCCTGYYCFQGSHVPFTFGQGTK [SEQ ID NO: 422] AGCTCGCCCGTCACAAAGAGCTTCA LEIKACAGGGGAGAGTGTTGA [SEQ ID NO: 420] Without leader [SEQ ID NO: 415]:GACGTCGTGATGACACAGTCCCCCC TGTCCCTGCCTGTGACCCTGGGACAGCCTGCCTCCATCTCCTGCAGATCC TCCCAGTCCATCCTGCACTCCAACGGCAACACCTACCTGGAATGGTTCCA GCAGCGGCCTGGCCAGTCTCCCAGACGGCTGATCTACAAGGTGTCCAACC GGTTCTCCGGCGTGCCCGACAGATTCTCCGGCTCTGGCTCTGGCACCGAC TTCACCCTGAAGATCTCCCGGGTGGAAGCCGAGGACGTGGGCGTGTACTA CTGTTTTCAAGGCTCCCACGTGCCCTTCACCTTCGGCCAGGGCACCAAGC TGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCA TCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAGCGAACTGTGGCTGCACCA LCzu2 423]: NO: 425]: GTCCTGCA TCCCCCCTGTCCCTGCCTTCTGTCTTCATCTTCCCG ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVVTCATCCTG GTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSILHSNGNTYLEWYQQRPGQ GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRLLICKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCT GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (Nucleo-CCCAGACTGCTGATCTGC TCGGGTAACTCCCAGGAG GGTATCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACTCCCAGACTGCTGATCTGCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID 423)AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 426]: [SEQ ID GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS NO: 427]TACTACTGTTTTCAAGGC CATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGCCRSSQSILHSNGNTYLEWYQQR TCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTCACCAAGCTGGAAATCAAACGAACTG PGQSPRLLICKVSNRFSGVPDR TTCGGCCAGGGCACCAAGAACAGGGGAGAGTGT TGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDVCTGGAAATCAAA (Nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAAGVYYCFQGSHVPFTFGQGTKLE (nucleotides 58 to to 714 of SEQ IDTCTGGAACTGCCTCTGTTGTGTGCC IKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO:NO: 423) TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 423)[SEQ ID NO: 430] GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS[SEQ ID NO: 428] RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCCTYSLSSTLTLSKADYEKHKVYA DVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPREAGGAGAGTGTCACAGAGCAGGACAG CEVTHQGLSSPVTKSFNRGEC ASISCRSSQSILHSNGNTAKVQWKVDNALQSGNSQE CAAGGACAGCACCTACAGCCTCAGC YLEWYQQRPGQSPRLLICSVTEQDSKDSTYSLSSTL AGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGSTLSKADYEKHKVYACEVT ACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGVHQGLSSPVTKSFNRGEC CTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK[SEQ ID NO: 431] AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA[SEQ ID NO: 429] Without leader [SEQ ID NO: 424]:GACGTCGTGATGACACAGTCCCCCC TGTCCCTGCCTGTGACCCTGGGACAGCCTGCCTCCATCTCCTGCAGATCC TCCCAGTCCATCCTGCACTCCAACGGCAACACCTACCTGGAATGGTATCA GCAGCGGCCTGGCCAGTCTCCCAGACTGCTGATCTGCAAGGTGTCCAACC GGTTCTCCGGCGTGCCCGACAGATTCTCCGGCTCTGGCTCTGGCACCGAC TTCACCCTGAAGATCTCCCGGGTGGAAGCCGAGGACGTGGGCGTGTACTA CTGTTTTCAAGGCTCCCACGTGCCCTTCACCTTCGGCCAGGGCACCAAGC TGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCA TCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAGCGAACTGTGGCTGCACCA LCzu3 432]: NO: 434]: GTCCTGCA TCCCCCCTGTCCCTGCCTTCTGTCTTCATCTTCCCG ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVVTCATCCTG GTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSILHSNGNTYLEWFQQRPGQ GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRRLICKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTTCCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCT GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCCGTAGACTGATCTGC TCGGGTAACTCCCAGGAG GGTTCCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACTCCCCGTAGACTGATCTGCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 432) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 435]: NO: 436] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWFQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRRLICKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 432)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 432) [SEQ ID NO: 439]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 437]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWFQQRPGQSPRRLIC SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 440]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 438]Without leader [SEQ ID NO: 433]: GACGTCGTGATGACACAGTCCCCCCTGTCCCTGCCTGTGACCCTGGGACA GCCTGCCTCCATCTCCTGCAGATCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTTCCAGCAGCGGCCTGGCCAGTCTCCCCGT AGACTGATCTGCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAGATCTCCCGGGTGG AAGCCGAGGACGTGGGCGTGTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG 7G6- AGAGTGTTGA With leader [SEQ ID ATGGGCTGGACGTCGTGATGACACAG CGAACTGTGGCTGCACCA LCzu4 With leader [SEQ ID NO:NO: 443]: GTCCTGCA TCCCCCCTGTCCCTGCCT TCTGTCTTCATCTTCCCG 441]:MGWSCIILFLVATATGVHSDVV TCATCCTG GTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTGATGGGCTGGTCCTGCATCATCCTGT MTQSPLSLPVTLGQPASISCRS TTTCTGGTGCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCT TTCTGGTGGCCACCGCCACCGGCGTSQSILHSNGNTYLEWYQQRPGQ GGCCACCG TCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAATGCACAGCGACGTCGTGATGACACAG SPRRLICKVSNRFSGVPDRFSG CCACCGGCCACTCCAACGGCAACACC AACTTCTATCCCAGAGAG TCCCCCCTGTCCCTGCCTGTGACCCSGSGTDFTLKISRVEAEDVGVY GTGCACAG TACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAGTGGGACAGCCTGCCTCCATCTCCTG YCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCCGTGGATAACGCCCTCCAA CAGATCCTCCCAGTCCATCCTGCAC TVAAPSVFIFPPSDEQLKSGTA(nucleo- CCCAGACGGCTGATCTGC TCGGGTAACTCCCAGGAG TCCAACGGCAACACCTACCTGGAATSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACGGTATCAGCAGCGGCCTGGCCAGTC ALQSGNSQESVTEQDSKDSTYS to 57 ofTCTGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC CCCCAGACGGCTGATCTGCAAGGTGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGTCCAACCGGTTCTCTGGCGTGCCCG THQGLSSPVTKSFNRGEC NO: 441) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC ACAGATTCTCCGGCTCTGGCTCTGG Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CACCGACTTCACCCTGAAGATCTCCNO: 444]: NO: 445] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCCGGGTGGAAGCCGAGGACGTGGGCG DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG TGTACTACTGTTTTCAAGGCTCCCA CRSSQSILHSNGNTYLEWYQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC CGTGCCCTTCACCTTCGGCCAGGGCPGQSPRRLICKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTACCAAGCTGGAAATCAAACGAACTG FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 TGGCTGCACCATCTGTCTTCATCTT GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID CCCGCCATCTGATGAGCAGTTGAAAIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 441)TCTGGAACTGCCTCTGTTGTGTGCC GTASVVCLLNNFYPREAKVQWK 441) [SEQ ID NO: 448]TGCTGAATAACTTCTATCCCAGAGA VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 446]RTVAAPSVFIFPPSDEQL GGCCAAAGTACAGTGGAAGGTGGAT TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AACGCCCTCCAATCGGGTAACTCCCCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSILHSNGNT AKVQWKVDNALQSGNSQEAGGAGAGTGTCACAGAGCAGGACAG YLEWYQQRPGQSPRRLIC SVTEQDSKDSTYSLSSTLCAAGGACAGCACCTACAGCCTCAGC KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTAGCACCCTGACGCTGAGCAAAGCAG GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECACTACGAGAAACACAAAGTCTACGC YYCFQGSHVPFTFGQGTK [SEQ ID NO: 449]CTGCGAAGTCACCCATCAGGGCCTG LEIK AGCTCGCCCGTCACAAAGAGCTTCA[SEQ ID NO: 447] ACAGGGGAGAGTGTTGA Without leader [SEQ ID NO: 442]:GACGTCGTGATGACACAGTCCCCCC TGTCCCTGCCTGTGACCCTGGGACAGCCTGCCTCCATCTCCTGCAGATCC TCCCAGTCCATCCTGCACTCCAACGGCAACACCTACCTGGAATGGTATCA GCAGCGGCCTGGCCAGTCCCCCAGACGGCTGATCTGCAAGGTGTCCAACC GGTTCTCTGGCGTGCCCGACAGATTCTCCGGCTCTGGCTCTGGCACCGAC TTCACCCTGAAGATCTCCCGGGTGGAAGCCGAGGACGTGGGCGTGTACTA CTGTTTTCAAGGCTCCCACGTGCCCTTCACCTTCGGCCAGGGCACCAAGC TGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCA TCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAGCGAACTGTGGCTGCACCA LCzu5 450]: NO: 452]: GTCCTGCA TCCCCCCTGTCCCTGCCTTCTGTCTTCATCTTCCCG ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVVTCATCCTG GTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSILHSNGNTYLEWFQQRPGQ GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRLLICKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTTCCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCAGACTGCTGATCTGC TCGGGTAACTCCCAGGAG GGTTCCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCCAGACTGCTGATCTGCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 450) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 453]: NO: 454] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWFQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRLLICKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 450)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 450) [SEQ ID NO: 457]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 455]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWFQQRPGQSPRLLIC SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 458]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 456]Without leader [SEQ ID NO: 451]: GACGTCGTGATGACACAGTCCCCCCTGTCCCTGCCTGTGACCCTGGGACA GCCTGCCTCCATCTCCTGCAGATCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTTCCAGCAGCGGCCTGGCCAGTCCCCCAGA CTGCTGATCTGCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAGATCTCCCGGGTGG AAGCCGAGGACGTGGGCGTGTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAG CGAACTGTGGCTGCACCA LCzu6459]: NO: 461]: GTCCTGCA TCCCCCCTGTCCCTGCCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVV TCATCCTGGTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSILHSNGNTYLEWYQQRPGQ GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRLLISKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCT GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCCGGCTGCTGATTTCC TCGGGTAACTCCCAGGAG GGTATCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACTCCCCGGCTGCTGATTTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 OFTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 459) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 462]: NO: 463] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWYQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRLLISKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 459)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 459) [SEQ ID NO: 466]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 464]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWYQQRPGQSPRLLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 467]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 465]Without leader [SEQ ID NO: 460]: GACGTCGTGATGACACAGTCCCCCCTGTCCCTGCCTGTGACCCTGGGACA GCCTGCCTCCATCTCCTGCAGATCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTATCAGCAGCGGCCTGGCCAGTCTCCCCGG CTGCTGATTTCCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAGATCTCCCGGGTGG AAGCCGAGGACGTGGGCGTGTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAG CGAACTGTGGCTGCACCA LCzu7468]: NO: 470]: GTCCTGCA TCCCCCCTGTCCCTGCCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVV TCATCCTGGTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSILHSNGNTYLEWFQQRPGQ GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRRLISKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTTCCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCT GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCAGACGGCTGATCTCC TCGGGTAACTCCCAGGAG GGTTCCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACTCCCAGACGGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 468) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 471]: NO: 472] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWFQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRRLISKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 468)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 468) [SEQ ID NO: 475]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 473]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWFQQRPGQSPRRLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 476]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 474]Without leader [SEQ ID NO: 469]: GACGTCGTGATGACACAGTCCCCCCTGTCCCTGCCTGTGACCCTGGGACA GCCTGCCTCCATCTCCTGCAGATCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTTCCAGCAGCGGCCTGGCCAGTCTCCCAGA CGGCTGATCTCCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAGATCTCCCGGGTGG AAGCCGAGGACGTGGGCGTGTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAG CGAACTGTGGCTGCACCA LCzu8477]: NO: 479]: GTCCTGCA TCCCCCCTGTCCCTGCCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVV TCATCCTGGTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSIVHSNGNTYLEWFQQRPGQ GGCCACCGTCCTCCCAGTCCATCGTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRRLISKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTTCCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCGTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCT GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCAGACGGCTGATCTCC TCGGGTAACTCCCAGGAG GGTTCCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACTCCCAGACGGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 477) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 480]: NO: 481] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSIVHSNGNTYLEWFQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRRLISKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 477)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 477) RTVAAPSVFIFPPSDEQLGGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 482]KSGTASVVCLLNNFYPRE AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP AKVQWKVDNALQSGNSQE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSIVHSNGNT SVTEQDSKDSTYSLSSTLCAAGGACAGCACCTACAGCCTCAGC YLEWFQQRPGQSPRRLIS TLSKADYEKHKVYACEVTAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS HQGLSSPVTKSFNRGECACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV [SEQ ID NO: 484]CTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK AGCTCGCCCGTCACAAAGAGCTTCALEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 483] Without leader [SEQ ID NO: 478]:GACGTCGTGATGACACAGTCCCCCC TGTCCCTGCCTGTGACCCTGGGACAGCCTGCCTCCATCTCCTGCAGATCC TCCCAGTCCATCGTGCACTCCAACGGCAACACCTACCTGGAATGGTTCCA GCAGCGGCCTGGCCAGTCTCCCAGACGGCTGATCTCCAAGGTGTCCAACC GGTTCTCCGGCGTGCCCGACAGATTCTCCGGCTCTGGCTCTGGCACCGAC TTCACCCTGAAGATCTCCCGGGTGGAAGCCGAGGACGTGGGCGTGTACTA CTGTTTTCAAGGCTCCCACGTGCCCTTCACCTTCGGCCAGGGCACCAAGC TGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCA TCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAGCGAACTGTGGCTGCACCA LCzu9 485]: NO: 487]: GTCCTGCA TCCCCCCTGTCCCTGCCTTCTGTCTTCATCTTCCCG ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVVTCATCCTG GTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSIVHSNGNTYLNWFQQRPGQ GGCCACCGTCCTCCCAGTCCATCGTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRRLISKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGAACTGGTTCCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCGTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCT GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGAACT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCAGACGGCTGATCTCC TCGGGTAACTCCCAGGAG GGTTCCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACTCCCAGACGGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 485) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 488]: NO: 489] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSIVHSNGNTYLNWFQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRRLISKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 485)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 485) [SEQ ID NO: 492]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 490]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSIVHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLNWFQQRPGQSPRRLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 493]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 491]Without leader [SEQ ID NO: 486]: GACGTCGTGATGACACAGTCCCCCCTGTCCCTGCCTGTGACCCTGGGACA GCCTGCCTCCATCTCCTGCAGATCCTCCCAGTCCATCGTGCACTCCAACG GCAACACCTACCTGAACTGGTTCCAGCAGCGGCCTGGCCAGTCTCCCAGA CGGCTGATCTCCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAGATCTCCCGGGTGG AAGCCGAGGACGTGGGCGTGTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAG CGAACTGTGGCTGCACCALCzu10 494]: NO: 496]: GTCCTGCA TCCCCCCTGTCCCTGCCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVV TCATCCTGGTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSIVHSNGNTYLEWFQQRPGQ GGCCACCGTCCTCCCAGTCCATCGTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRRLIYKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTTCCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCGTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCT GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCAGACGGCTGATCTAC TCGGGTAACTCCCAGGAG GGTTCCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACTCCCAGACGGCTGATCTACAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 494) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 497]: NO: 498] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSIVHSNGNTYLEWFQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRRLIYKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 494)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 494) [SEQ ID NO: 501]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 499]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSIVHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWFQQRPGQSPRRLIY SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 502]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 500]Without leader [SEQ ID NO: 495]: GACGTCGTGATGACACAGTCCCCCCTGTCCCTGCCTGTGACCCTGGGACA GCCTGCCTCCATCTCCTGCAGATCCTCCCAGTCCATCGTGCACTCCAACG GCAACACCTACCTGGAATGGTTCCAGCAGCGGCCTGGCCAGTCTCCCAGA CGGCTGATCTACAAGGTGTCCAACCGGTTCTCCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAGATCTCCCGGGTGG AAGCCGAGGACGTGGGCGTGTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GATATCCAGATGACCCAG GATATCCAGATGACCCAGLCzu11 503]: NO: 505]: GTCCTGCA TCCCCTTCCAGCCTGTCC TCCCCTTCCAGCCTGTCCATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDIQ TCATCCTGGCCTCTGTGGGCGACAGA GCCTCTGTGGGCGACAGA TTCTGGTGGCCACCGCCACCGGCGTMTQSPSSLSASVGDRVTITCRS TTTCTGGT GTGACCATCACCTGTCGG GTGACCATCACCTGTCGGGCACAGCGATATCCAGATGACCCAG SQSILHSNGNTYLEWYQQKPGK GGCCACCGTCCTCCCAGTCCATCCTG TCCTCCCAGTCCATCCTG TCCCCTTCCAGCCTGTCCGCCTCTGAPKLLIYKVSNRFSGVPSRFSG CCACCGGC CACTCCAACGGCAACACC CACTCCAACGGCAACACCTGGGCGACAGAGTGACCATCACCTG SGSGTDFTLTISSLQPEDFATY GTGCACAGTACCTGGAATGGTATCAG TACCTGGAATGGTATCAG TCGGTCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGAAGCCCGGCAAGGCC CAGAAGCCCGGCAAGGCCTCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCTAAGCTGCTGATCTAC CCTAAGCTGCTGATCTAC GGTATCAGCAGAAGCCCGGCAAGGCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AAGGTGTCCAACCGGTTCCCCTAAGCTGCTGATCTACAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCTCCAGA TCCGGCGTGCCCTCCAGA TCCAACCGGTTCTCCGGCGTGCCCTLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT TTCTCCGGCTCTGGCTCTCCAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 503) GGCACCGACTTCACCCTGGGCACCGACTTCACCCTG CACCGACTTCACCCTGACCATCTCC Without leader [SEQ ID[SEQ ID ACCATCTCCAGCCTCCAG ACCATCTCCAGCCTCCAG AGCCTCCAGCCCGAGGACTTCGCCANO: 506]: NO: 507] CCCGAGGACTTCGCCACC CCCGAGGACTTCGCCACCCCTACTACTGTTTTCAAGGCTCCCA DIQMTQSPSSLSASVGDRVTIT TACTACTGTTTTCAAGGCTACTACTGTTTTCAAGGC CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWYQQKTCCCACGTGCCCTTCACC TCCCACGTGCCCTTCACC ACCAAGCTGGAAATCAAACGAACTGPGKAPKLLIYKVSNRFSGVPSR TTCGGCCAGGGCACCAAG TTCGGCCAGGGCACCAAGTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLTISSLQPEDF CTGGAAATCAAACTGGAAATCAAACGAACT CCCGCCATCTGATGAGCAGTTGAAA ATYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to GTGGCTGCACCATCTGTC TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: TTCATCTTCCCGCCATCTTGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 503) GATGAGCAGTTGAAATCTGGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 508]GGAACTGCCTCTGTTGTG AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADIQMTQSPSSLSASVGDR TGCCTGCTGAATAACTTC AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC VTITCRSSQSILHSNGNT TATCCCAGAGAGGCCAAACAAGGACAGCACCTACAGCCTCAGC YLEWYQQKPGKAPKLLIY GTACAGTGGAAGGTGGATAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPSRFSGSGS AACGCCCTCCAATCGGGTACTACGAGAAACACAAAGTCTACGC GTDFTLTISSLOPEDFAT AACTCCCAGGAGAGTGTCCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK ACAGAGCAGGACAGCAAGAGCTCGCCCGTCACAAAGAGCTTCA LEIK GACAGCACCTACAGCCTC ACAGGGGAGAGTGTTGA[SEQ ID NO: 509] AGCAGCACCCTGACGCTG Without leader [SEQ IDAGCAAAGCAGACTACGAG NO: 504]: AAACACAAAGTCTACGCCGATATCCAGATGACCCAGTCCCCTT TGCGAAGTCACCCATCAG CCAGCCTGTCCGCCTCTGTGGGCGAGGCCTGAGCTCGCCCGTC CAGAGTGACCATCACCTGTCGGTCC ACAAAGAGCTTCAACAGGTCCCAGTCCATCCTGCACTCCAACG GGAGAGTGT GCAACACCTACCTGGAATGGTATCA(nucleotides 394 GCAGAAGCCCGGCAAGGCCCCTAAG to 714 of SEQ IDCTGCTGATCTACAAGGTGTCCAACC NO: 503) GGTTCTCCGGCGTGCCCTCCAGATT[SEQ ID NO: 510] CTCCGGCTCTGGCTCTGGCACCGAC RTVAAPSVFIFPPSDEQLTTCACCCTGACCATCTCCAGCCTCC KSGTASVVCLLNNFYPRE AGCCCGAGGACTTCGCCACCTACTAAKVQWKVDNALQSGNSQE CTGTTTTCAAGGCTCCCACGTGCCC SVTEQDSKDSTYSLSSTLTTCACCTTCGGCCAGGGCACCAAGC TLSKADYEKHKVYACEVT TGGAAATCAAACGAACTGTGGCTGCHQGLSSPVTKSFNRGEC ACCATCTGTCTTCATCTTCCCGCCA [SEQ ID NO: 511]TCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GACGTGCAGATGACCCAG CGAACTGTGGCTGCACCALCzu12 512]: NO: 514] GTCCTGCA TCCCCTTCCAGCCTGTCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVQ TCATCCTGGCCTCCGTGGGCGACAGA CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPSSLSASVGDRVTITCRS TTTCTGGT GTGACCATCACCTGTCGG AAATCTGGAACTGCCTCTGCACAGCGACGTGCAGATGACCCAG SQSILHSNGNTYLEWYQQKPGK GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCTTCCAGCCTGTCTGCCTCCGAPKLLICKVSNRFSGVPSRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGCGACAGAGTGACCATCACCTG SGSGTDFTLTISSLQPEDFATY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG TCGGTCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGAAGCCCGGCAAGGCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCTAAGCTGCTGATCTGC TCGGGTAACTCCCAGGAG GGTATCAGCAGAAGCCCGGCAAGGCSVVCLLNNFYPREAKVQWKVDN tides AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCTAAGCTGCTGATCTGCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCTCCAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCTLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGCCAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 512) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGACCATCTCC Without leader [SEQ ID[SEQ ID ACCATCTCCAGCCTCCAG TACGAGAAACACAAAGTC AGCCTCCAGCCCGAGGACTTCGCCANO: 515]: NO: 516] CCCGAGGACTTCGCCACC TACGCCTGCGAAGTCACCCCTACTACTGTTTTCAAGGCTCCCA DVQMTQSPSSLSASVGDRVTIT TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWYQQKTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGKAPKLLICKVSNRFSGVPSR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLTISSLQPEDF CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA ATYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 512)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 512) [SEQ ID NO: 519]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 517]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVQMTQSPSSLSASVGDR KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC VTITCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWYQQKPGKAPKLLIC SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPSRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLTISSLQPEDFAT HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 520]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 518]Without leader [SEQ ID NO: 513]: GACGTGCAGATGACCCAGTCCCCTTCCAGCCTGTCTGCCTCCGTGGGCGA CAGAGTGACCATCACCTGTCGGTCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAG CTGCTGATCTGCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCTCCAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGACCATCTCCAGCCTCC AGCCCGAGGACTTCGCCACCTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GACGTGCAGATGACCCAG CGAACTGTGGCTGCACCALCzu13 521]: NO: 523]: GTCCTGCA TCCCCTTCCAGCCTGTCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVQ TCATCCTGGCCTCCGTGGGCGACAGA CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPSSLSASVGDRVTITCRS TTTCTGGT GTGACCATCACCTGTCGG AAATCTGGAACTGCCTCTGCACAGCGACGTGCAGATGACCCAG SQSILHSNGNTYLEWYQQKPGK GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCTTCCAGCCTGTCTGCCTCCGAPKLLIYKVSNRFSGVPSRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGCGACAGAGTGACCATCACCTG SGSGTDFTLTISSLQPEDFATY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG TCGGTCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGAAGCCCGGCAAGGCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCTAAGCTGCTGATCTAC TCGGGTAACTCCCAGGAG GGTATCAGCAGAAGCCCGGCAAGGCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCTAAGCTGCTGATCTACAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCTCCAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCTLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGCCAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 521) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGACCATCTCC Without leader [SEQ ID[SEQ ID ACCATCTCCAGCCTCCAG TACGAGAAACACAAAGTC AGCCTCCAGCCCGAGGACTTCGCCANO: 524]: NO: 525] CCCGAGGACTTCGCCACC TACGCCTGCGAAGTCACCCCTACTACTGTTTTCAAGGCTCCCA DVQMTQSPSSLSASVGDRVTIT TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWYQQKTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGKAPKLLIYKVSNRFSGVPSR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLTISSLQPEDF CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA ATYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 521)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 521) [SEQ ID NO: 528]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 526]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVQMTQSPSSLSASVGDR KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC VTITCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWYQQKPGKAPKLLIY SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPSRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLTISSLOPEDFAT HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 529]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 527]Without leader [SEQ ID NO: 522]: GACGTGCAGATGACCCAGTCCCCTTCCAGCCTGTCTGCCTCCGTGGGCGA CAGAGTGACCATCACCTGTCGGTCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAG CTGCTGATCTACAAGGTGTCCAACCGGTTCTCCGGCGTGCCCTCCAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGACCATCTCCAGCCTCC AGCCCGAGGACTTCGCCACCTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GATATCCAGATGACCCAG CGAACTGTGGCTGCACCALCzu14 530]: NO: 532]: GTCCTGCA TCCCCTTCCAGCCTGTCC TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDIQ TCATCCTGGCCTCTGTGGGCGACAGA CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPSSLSASVGDRVTITCRS TTTCTGGT GTGACCATCACCTGTCGG AAATCTGGAACTGCCTCTGCACAGCGATATCCAGATGACCCAG SQSILHSNGNTYLEWYQQKPGK GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCTTCCAGCCTGTCCGCCTCTGAPKLLICKVSNRFSGVPSRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGCGACAGAGTGACCATCACCTG SGSGTDFTLTISSLOPEDFATY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG TCGGTCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGAAGCCCGGCAAGGCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCTAAGCTGCTGATCTGC TCGGGTAACTCCCAGGAG GGTATCAGCAGAAGCCCGGCAAGGCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCTAAGCTGCTGATCTGCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCTCCAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCTLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGCCAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 530) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGACCATCTCC Without leader [SEQ ID[SEQ ID ACCATCTCCAGCCTCCAG TACGAGAAACACAAAGTC AGCCTCCAGCCCGAGGACTTCGCCANO: 533]: NO: 534] CCCGAGGACTTCGCCACC TACGCCTGCGAAGTCACCCCTACTACTGTTTTCAAGGCTCCCA DIQMTQSPSSLSASVGDRVTIT TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWYQQKTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGKAPKLLICKVSNRFSGVPSR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGATGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLTISSLQPEDF CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA ATYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 530)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 530) [SEQ ID NO: 537]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 535]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADIQMTQSPSSLSASVGDR KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC VTITCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWYQQKPGKAPKLLIC SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPSRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLTISSLOPEDFAT HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 538]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 536]Without leader [SEQ ID NO: 531]: GATATCCAGATGACCCAGTCCCCTTCCAGCCTGTCCGCCTCTGTGGGCGA CAGAGTGACCATCACCTGTCGGTCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAG CTGCTGATCTGCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCTCCAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGACCATCTCCAGCCTCC AGCCCGAGGACTTCGCCACCTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID O: ATGGGCTG GACGTGCAGATGACCCAG CGAACTGTGGCTGCACCALCzu15 539]: 541]: GTCCTGCA TCCCCTTCCAGCCTGTCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVQ TCATCCTGGCCTCCGTGGGCGACAGA CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPSSLSASVGDRVTITCRS TTTCTGGT GTGACCATCACCTGTCGG AAATCTGGAACTGCCTCTGCACAGCGACGTGCAGATGACCCAG SQSILHSNGNTYLEWYQQKPGK GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCTTCCAGCCTGTCTGCCTCCGAPKLLISKVSNRFSGVPSRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGCGACAGAGTGACCATCACCTG SGSGTDFTLTISSLOPEDFATY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG TCGGTCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGAAGCCCGGCAAGGCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleotCCTAAGCTGCTGATCTCC TCGGGTAACTCCCAGGAG GGTATCAGCAGAAGCCCGGCAAGGCSVVCLLNNFYPREAKVQWKVDN ides: AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCTAAGCTGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCTCCAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCTLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGCCAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 539) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGACCATCTCC Without leader [SEQ ID[SEQ ID ACCATCTCCAGCCTCCAG TACGAGAAACACAAAGTC AGCCTCCAGCCCGAGGACTTCGCCANO: 542]: NO: 543] CCCGAGGACTTCGCCACC TACGCCTGCGAAGTCACCCCTACTACTGTTTTCAAGGCTCCCA DVQMTQSPSSLSASVGDRVTIT TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWYQQKTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGKAPKLLISKVSNRFSGVPSR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLTISSLQPEDF CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA ATYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 539)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 539) [SEQ ID NO: 546]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 544]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVQMTQSPSSLSASVGDR KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC VTITCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWYQQKPGKAPKLLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPSRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLTISSLOPEDFAT HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 547]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 545]Without leader [SEQ ID NO: 540]: GACGTGCAGATGACCCAGTCCCCTTCCAGCCTGTCTGCCTCCGTGGGCGA CAGAGTGACCATCACCTGTCGGTCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAG CTGCTGATCTCCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCTCCAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGACCATCTCCAGCCTCC AGCCCGAGGACTTCGCCACCTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAG 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GACGTGCAGATGACCCAGCGAACTGTGGCTGCACCA LCzu16 548]: NO: 550]: GTCCTGCA TCCCCTTCCAGCCTGTCTTCTGTCTTCATCTTCCCG ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVQTCATCCTG GCCTCCGTGGGCGACAGA CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPSSLSASVGDRVTITCRS TTTCTGGT GTGACCATCACCTGTCGG AAATCTGGAACTGCCTCTGCACAGCGACGTGCAGATGACCCAG SQSIVHSNGNTYLEWYQQKPGK GGCCACCGTCCTCCCAGTCCATCGTG GTTGTGTGCCTGCTGAAT TCCCCTTCCAGCCTGTCTGCCTCCGAPKLLISKVSNRFSGVPSRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGCGACAGAGTGACCATCACCTG SGSGTDFTLTISSLOPEDFATY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG TCGGTCCTCCCAGTCCATCGTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGAAGCCCGGCAAGGCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCTAAGCTGCTGATCTCC TCGGGTAACTCCCAGGAG GGTATCAGCAGAAGCCCGGCAAGGCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCTAAGCTGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCTCCAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCTLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGCCAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 548) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGACCATCTCC Without leader [SEQ ID[SEQ ID ACCATCTCCAGCCTCCAG TACGAGAAACACAAAGTC AGCCTCCAGCCCGAGGACTTCGCCANO: 551]: NO: 552] CCCGAGGACTTCGCCACC TACGCCTGCGAAGTCACCCCTACTACTGTTTTCAAGGCTCCCA DVQMTQSPSSLSASVGDRVTIT TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSIVHSNGNTYLEWYQQKTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGKAPKLLISKVSNRFSGVPSR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLTISSLQPEDF CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA ATYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 548)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 548) [SEQ ID NO: 555]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 553]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVQMTQSPSSLSASVGDR KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC VTITCRSSQSIVHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWYQQKPGKAPKLLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPSRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLTISSLOPEDFAT HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 556]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 554]Without leader [SEQ ID NO: 549]: GACGTGCAGATGACCCAGTCCCCTTCCAGCCTGTCTGCCTCCGTGGGCGA CAGAGTGACCATCACCTGTCGGTCCTCCCAGTCCATCGTGCACTCCAACG GCAACACCTACCTGGAATGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAG CTGCTGATCTCCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCTCCAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGACCATCTCCAGCCTCC AGCCCGAGGACTTCGCCACCTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GACGTGCAGATGACCCAG CGAACTGTGGCTGCACCALCzu17 557]: NO: 559]: GTCCTGCA TCCCCTTCCAGCCTGTCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVQ TCATCCTGGCCTCCGTGGGCGACAGA CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPSSLSASVGDRVTITCRS TTTCTGGT GTGACCATCACCTGTCGG AAATCTGGAACTGCCTCTGCACAGCGACGTGCAGATGACCCAG SQSIVHSNGNTYLNWYQQKPGK GGCCACCGTCCTCCCAGTCCATCGTG GTTGTGTGCCTGCTGAAT TCCCCTTCCAGCCTGTCTGCCTCCGAPKLLISKVSNRFSGVPSRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGCGACAGAGTGACCATCACCTG SGSGTDFTLTISSLOPEDFATY GTGCACAGTACCTGAACTGGTATCAG GCCAAAGTACAGTGGAAG TCGGTCCTCCCAGTCCATCGTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGAAGCCCGGCAAGGCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGAACT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCTAAGCTGCTGATCTCC TCGGGTAACTCCCAGGAG GGTATCAGCAGAAGCCCGGCAAGGCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCTAAGCTGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCTCCAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCTLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGCCAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 557) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGACCATCTCC Without leader [SEQ ID[SEQ ID ACCATCTCCAGCCTCCAG TACGAGAAACACAAAGTC AGCCTCCAGCCCGAGGACTTCGCCANO: 560]: NO: 561] CCCGAGGACTTCGCCACC TACGCCTGCGAAGTCACCCCTACTACTGTTTTCAAGGCTCCCA DVQMTQSPSSLSASVGDRVTIT TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSIVHSNGNTYLNWYQQKTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGKAPKLLISKVSNRFSGVPSR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGATGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLTISSLQPEDF CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA ATYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 557)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 557) [SEQ ID NO: 564]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 562]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVQMTQSPSSLSASVGDR KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC VTITCRSSQSIVHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLNWYQQKPGKAPKLLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPSRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLTISSLQPEDFAT HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 565]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 563]Without leader [SEQ ID NO: 558]: GACGTGCAGATGACCCAGTCCCCTTCCAGCCTGTCTGCCTCCGTGGGCGA CAGAGTGACCATCACCTGTCGGTCCTCCCAGTCCATCGTGCACTCCAACG GCAACACCTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAG CTGCTGATCTCCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCTCCAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGACCATCTCCAGCCTCC AGCCCGAGGACTTCGCCACCTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GATATCCAGATGACCCAG CGAACTGTGGCTGCACCALCzu18 566]: NO: 568]: GTCCTGCA TCCCCTTCCAGCCTGTCC TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDIQ TCATCCTGGCCTCTGTGGGCGACAGA CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPSSLSASVGDRVTITCRS TTTCTGGT GTGACCATCACCTGTCGG AAATCTGGAACTGCCTCTGCACAGCGATATCCAGATGACCCAG SQSILHSNGNTYLEWYQQKPGK GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCTTCCAGCCTGTCCGCCTCTGAPKLLISKVSNRFSGVPSRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGCGACAGAGTGACCATCACCTG SGSGTDFTLTISSLOPEDFATY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG TCGGTCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGAAGCCCGGCAAGGCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCTAAGCTGCTGATCTCC TCGGGTAACTCCCAGGAG GGTATCAGCAGAAGCCCGGCAAGGCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCTAAGCTGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCTCCAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCTLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGCCAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 566) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGACCATCTCC Without leader [SEQ ID[SEQ ID ACCATCTCCAGCCTCCAG TACGAGAAACACAAAGTC AGCCTCCAGCCCGAGGACTTCGCCANO: 569]: NO: 570] CCCGAGGACTTCGCCACC TACGCCTGCGAAGTCACCCCTACTACTGTTTTCAAGGCTCCCA DIQMTQSPSSLSASVGDRVTIT TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWYQQKTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGKAPKLLISKVSNRFSGVPSR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGATGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLTISSLQPEDF CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA ATYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 566) [SEQ IDTGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 566) NO: 573]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 571]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADIQMTQSPSSLSASVGDR KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC VTITCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWYQQKPGKAPKLLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPSRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLTISSLQPEDFAT HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 574]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 572]NO: 567]: GATATCCAGATGACCCAGTCCCCTT CCAGCCTGTCCGCCTCTGTGGGCGACAGAGTGACCATCACCTGTCGGTCC TCCCAGTCCATCCTGCACTCCAACGGCAACACCTACCTGGAATGGTATCA GCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTCCAAGGTGTCCAACC GGTTCTCCGGCGTGCCCTCCAGATTCTCCGGCTCTGGCTCTGGCACCGAC TTCACCCTGACCATCTCCAGCCTCCAGCCCGAGGACTTCGCCACCTACTA CTGTTTTCAAGGCTCCCACGTGCCCTTCACCTTCGGCCAGGGCACCAAGC TGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCA TCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGC CCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6-With leader [SEQ ID NO: With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAGCGAACTGTGGCTGCACCA LCzu21 575]: NO: 577]: GTCCTGCA TCCCCCCTGTCCCTGCCTTCTGTCTTCATCTTCCCG ATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVVTCATCCTG GTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSILHSNGNTYLEWFQQRPGQ GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRLLISKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTTCCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCAGACTGCTGATCTCC TCGGGTAACTCCCAGGAG GGTTCCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides 1 AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCCAGACTGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCCGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCCGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 575) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 578]: NO: 579] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWFQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRLLISKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 575)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 575) [SEQ ID NO: 582]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 580]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWFQQRPGQSPRLLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 583]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 581]Without leader [SEQ ID NO: 576]: GACGTCGTGATGACACAGTCCCCCCTGTCCCTGCCTGTGACCCTGGGACA GCCTGCCTCCATCTCCTGCAGATCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTTCCAGCAGCGGCCTGGCCAGTCCCCCAGA CTGCTGATCTCCAAGGTGTCCAACCGGTTCTCCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAGATCTCCCGGGTGG AAGCCGAGGACGTGGGCGTGTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6- With leader [SEQ ID NO:With leader [SEQ ID ATGGGCTG GACGTCGTGATGACACAG CGAACTGTGGCTGCACCALCzu22 584]: NO: 586]: GTCCTGCA TCCCCCCTGTCCCTGCCT TCTGTCTTCATCTTCCCGATGGGCTGGTCCTGCATCATCCTGT MGWSCIILFLVATATGVHSDVV TCATCCTGGTGACCCTGGGACAGCCT CCATCTGATGAGCAGTTG TTCTGGTGGCCACCGCCACCGGCGTMTQSPLSLPVTLGQPASISCRS TTTCTGGT GCCTCCATCTCCTGCAGA AAATCTGGAACTGCCTCTGCACAGCGACGTCGTGATGACACAG SQSILHSNGNTYLEWYQQRPGQ GGCCACCGTCCTCCCAGTCCATCCTG GTTGTGTGCCTGCTGAAT TCCCCCCTGTCCCTGCCTGTGACCCSPRRLISKVSNRFSGVPDRFSG CCACCGGC CACTCCAACGGCAACACC AACTTCTATCCCAGAGAGTGGGACAGCCTGCCTCCATCTCCTG SGSGTDFTLKISRVEAEDVGVY GTGCACAGTACCTGGAATGGTATCAG GCCAAAGTACAGTGGAAG CAGATCCTCCCAGTCCATCCTGCACYCFQGSHVPFTFGQGTKLEIKR C CAGCGGCCTGGCCAGTCC GTGGATAACGCCCTCCAATCCAACGGCAACACCTACCTGGAAT TVAAPSVFIFPPSDEQLKSGTA (nucleo-CCCAGACGGCTGATCTCC TCGGGTAACTCCCAGGAG GGTATCAGCAGCGGCCTGGCCAGTCSVVCLLNNFYPREAKVQWKVDN tides AAGGTGTCCAACCGGTTC AGTGTCACAGAGCAGGACCCCCAGACGGCTGATCTCCAAGGTG ALQSGNSQESVTEQDSKDSTYS to 57 ofTCTGGCGTGCCCGACAGA AGCAAGGACAGCACCTAC TCCAACCGGTTCTCTGGCGTGCCCGLSSTLTLSKADYEKHKVYACEV SEQ ID TTCTCCGGCTCTGGCTCT AGCCTCAGCAGCACCCTGACAGATTCTCCGGCTCTGGCTCTGG THQGLSSPVTKSFNRGEC NO: 584) GGCACCGACTTCACCCTGACGCTGAGCAAAGCAGAC CACCGACTTCACCCTGAAGATCTCC Without leader [SEQ ID[SEQ ID AAGATCTCCCGGGTGGAA TACGAGAAACACAAAGTC CGGGTGGAAGCCGAGGACGTGGGCGNO: 587]: NO: 588] GCCGAGGACGTGGGCGTG TACGCCTGCGAAGTCACCTGTACTACTGTTTTCAAGGCTCCCA DVVMTQSPLSLPVTLGQPASIS TACTACTGTTTTCAAGGCCATCAGGGCCTGAGCTCG CGTGCCCTTCACCTTCGGCCAGGGC CRSSQSILHSNGNTYLEWYQQRTCCCACGTGCCCTTCACC CCCGTCACAAAGAGCTTC ACCAAGCTGGAAATCAAACGAACTGPGQSPRRLISKVSNRFSGVPDR TTCGGCCAGGGCACCAAG AACAGGGGAGAGTGTTGGCTGCACCATCTGTCTTCATCTT FSGSGSGTDFTLKISRVEAEDV CTGGAAATCAAA(nucleotides 394 CCCGCCATCTGATGAGCAGTTGAAA GVYYCFQGSHVPFTFGQGTKLE(nucleotides 58 to to 714 of SEQ ID TCTGGAACTGCCTCTGTTGTGTGCCIKRTVAAPSVFIFPPSDEQLKS 393 of SEQ ID NO: NO: 584)TGCTGAATAACTTCTATCCCAGAGA GTASVVCLLNNFYPREAKVQWK 584) [SEQ ID NO: 591]GGCCAAAGTACAGTGGAAGGTGGAT VDNALQSGNSQESVTEQDSKDS [SEQ ID NO: 589]RTVAAPSVFIFPPSDEQL AACGCCCTCCAATCGGGTAACTCCC TYSLSSTLTLSKADYEKHKVYADVVMTQSPLSLPVTLGQP KSGTASVVCLLNNFYPRE AGGAGAGTGTCACAGAGCAGGACAGCEVTHQGLSSPVTKSFNRGEC ASISCRSSQSILHSNGNT AKVQWKVDNALQSGNSQECAAGGACAGCACCTACAGCCTCAGC YLEWYQQRPGQSPRRLIS SVTEQDSKDSTYSLSSTLAGCACCCTGACGCTGAGCAAAGCAG KVSNRFSGVPDRFSGSGS TLSKADYEKHKVYACEVTACTACGAGAAACACAAAGTCTACGC GTDFTLKISRVEAEDVGV HQGLSSPVTKSFNRGECCTGCGAAGTCACCCATCAGGGCCTG YYCFQGSHVPFTFGQGTK [SEQ ID NO: 592]AGCTCGCCCGTCACAAAGAGCTTCA LEIK ACAGGGGAGAGTGTTGA [SEQ ID NO: 590]Without leader [SEQ ID NO: 585]: GACGTCGTGATGACACAGTCCCCCCTGTCCCTGCCTGTGACCCTGGGACA GCCTGCCTCCATCTCCTGCAGATCCTCCCAGTCCATCCTGCACTCCAACG GCAACACCTACCTGGAATGGTATCAGCAGCGGCCTGGCCAGTCCCCCAGA CGGCTGATCTCCAAGGTGTCCAACCGGTTCTCTGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAGATCTCCCGGGTGG AAGCCGAGGACGTGGGCGTGTACTACTGTTTTCAAGGCTCCCACGTGCCC TTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAACGAACTGTGGCTGC ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTGA 7G6 VH numbered according to KabatClone Name (Species VH CDR1 VH CDR3 & VH CDR1 Acid Amino  VH CDR2VH CDR2 VH CDR3 Amino Acid Isotype) DNA Sequence Sequence DNA SequenceAmino Acid DNA Sequence Sequence mouse ACCTACTGGATA TYWITGATATTTATCCTGGTAGTAGTA DIYPGSSICNYNEK GAGGATGGTTACGACGCCTGGTTT EDGYDAWF7G6-Vh ACC [SEQ TTTGTAACTACAATGAGAAGTT FKS AY [SEQ ID NO: ID NO: CAAGAGC[SEQ ID NO: GCTTAC [SEQ ID 593] 594] [SEQ ID NO: 595] 596][SEQ ID NO: 597] NO: 598] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCADIYPGSSICNYNEK GAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu1 ACC [SEQTCTGCAACTACAACGAGAAGTT FKS GCCTAC AY [SEQ ID NO: ID NO: CAAGTCC[SEQ ID NO: [SEQ ID NO: 603] [SEQ ID 599] 600] [SEQ ID NO: 601] 602]NO: 604] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCA DIYPGSSICNYNEKGAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu2 ACC [SEQ TCTGCAACTACAACGAGAAGTTFKS GCCTAC AY [SEQ ID NO: ID NO: CAAGTCC [SEQ ID NO: [SEQ ID NO: 609][SEQ ID 605] 606] [SEQ ID NO: 607] 608] NO: 610] 7G6- ACCTACTGGATC TYWITGACATCTACCCCGGCTCCTCCA DIYPGSSICNYNEK GAGGACGGCTACGACGCTTGGTTT EDGYDAWFHCzu3 ACC [SEQ TCTGCAACTACAACGAGAAGTT FKS GCCTAC AY [SEQ ID NO: ID NO:CAAGTCC [SEQ ID NO: [SEQ ID NO: 615] [SEQ ID 611] 612] [SEQ ID NO: 613]614] NO: 616] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCADIYPGSSICNYAQK GAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu4 ACC [SEQTCTGCAACTACGCCCAGAAATT FQG GCCTAC AY [SEQ ID NO: ID NO: CCAGGGC[SEQ ID NO: [SEQ ID NO: 621] [SEQ ID 617] 618] [SEQ ID NO: 619] 620]NO: 622] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCA DIYPGSSISNYNEKGAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu5 ACC [SEQ TCTCCAACTACAACGAGAAGTTFKS AY [SEQ ID NO: ID NO: CAAGTCC [SEQ ID NO: GCCTAC [SEQ ID 623] 624][SEQ ID NO: 625] 626] [SEQ ID NO: 627] NO: 628] 7G6- ACCTACTGGATC TYWITGACATCTACCCCGGCTCCTCCA DIYPGSSISNYNEK GAGGACGGCTACGACGCTTGGTTT EDGYDAWFHCzu6 ACC [SEQ TCTCCAACTACAACGAGAAGTT FKS GCCTAC AY [SEQ ID NO: ID NO:CAAGTCC [SEQ ID NO: [SEQ ID NO: 633] [SEQ ID 629] 630] [SEQ ID NO: 631]632] NO: 634] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCADIYPGSSISNYAQK GAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu7 ACC [SEQTCTCCAACTACGCCCAGAAGTT FQG GCCTAC AY [SEQ ID NO: ID NO: CCAGGGC[SEQ ID NO: [SEQ ID NO: 639] [SEQ ID 635] 636] [SEQ ID NO: 637] 638]NO: 640] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCA DIYPGSSISNYAQKGAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu8 ACC [SEQ TCTCCAACTACGCCCAGAAGTTFQG AY [SEQ ID NO: ID NO: CCAGGGC [SEQ ID NO: GCCTAC [SEQ ID 641] 642][SEQ ID NO: 643] 644] [SEQ ID NO: 645] NO: 646] 7G6- ACCTACTGGATC TYWITGACATCTACCCCGGCTCCTCCA DIYPGSSICNYAQK GAGGACGGCTACGACGCTTGGTTT EDGYDAWFHCzu9 ACC [SEQ TCTGCAACTACGCCCAGAAGTT FQG GCCTAC AY [SEQ ID NO: ID NO:CCAGGGC [SEQ ID NO: [SEQ ID NO: 651] [SEQ ID 647] 648] [SEQ ID NO: 649]650] NO: 652] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCADIYPGSSICNYAQK GAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu10 ACC [SEQTCTGCAACTACGCCCAGAAGTT FQG GCCTAC AY [SEQ ID NO: ID NO: CCAGGGC[SEQ ID NO: [SEQ ID NO: 657] [SEQ ID 653] 654] [SEQ ID NO: 655] 656]NO: 658] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCA DIYPGSSICNYNEKGAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu11 ACC [SEQ TCTGCAACTACAACGAGAAGTTFKS AY [SEQ ID NO: ID NO: CAAGTCC [SEQ ID NO: GCCTAC [SEQ ID 659] 660][SEQ ID NO: 661] 662] [SEQ ID NO: 663] NO: 664] 7G6- ACCTACTGGATC TYWITGACATCTACCCCGGCTCCTCCA DIYPGSSICNYNEK GAGGACGGCTACGACGCTTGGTTT EDGYDAWFHCzu12 ACC [SEQ TCTGCAACTACAACGAGAAGTT FKS GCTTAC AY [SEQ ID NO: ID NO:CAAGTCC [SEQ ID NO: [SEQ ID NO: 669] [SEQ ID 665] 666] [SEQ ID NO: 667]668] NO: 670] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCADIYPGSSICNYADS GAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu13 ACC [SEQTCTGCAACTACGCCGACTCCGT VKG GCTTAC AY [SEQ ID NO: ID NO: CAAGGGC[SEQ ID NO: [SEQ ID NO: 675] [SEQ ID 671] 672] [SEQ ID NO: 673] 674]NO: 676] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCA DIYPGSSICNYADKGAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu14 ACC [SEQ TCTGCAACTACGCCGACAAGTTFKG AY [SEQ ID NO: ID NO: CAAGGGC [SEQ ID NO: GCTTAC [SEQ ID 677] 678][SEQ ID NO: 679] 680] [SEQ ID NO: 681] NO: 682] 7G6- ACCTACTGGATC TYWITGACATCTACCCCGGCTCCTCCA DIYPGSSICNYNEK GAGGACGGCTACGACGCTTGGTTT EDGYDAWFHCzu15 ACC [SEQ TCTGCAACTACAACGAGAAGTT FKS GCTTAC AY [SEQ ID NO: ID NO:CAAGTCC [SEQ ID NO: [SEQ ID NO: 687] [SEQ ID 683] 684] [SEQ ID NO: 685]686] NO: 688] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCADIYPGSSICNYNEK GAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu16 ACC [SEQTCTGCAACTACAACGAGAAGTT FKS AY [SEQ ID NO: ID NO: CAAGTCC [SEQ ID NO:GCTTAC [SEQ ID 689] 690] [SEQ ID NO: 691] 692] [SEQ ID NO: 693] NO: 694]7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCA DIYPGSSICNYNEKGAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu17 ACC [SEQ TCTGCAACTACAACGAGAAGTTFKS GCTTAC AY [SEQ ID NO: ID NO: CAAGTCC [SEQ ID NO: [SEQ ID NO: 699][SEQ ID 695] 696] [SEQ ID NO: 697] 698] NO: 700] 7G6- ACCTACTGGATC TYWITGACATCTACCCCGGCTCCTCCA DIYPGSSICNYNEK GAGGACGGCTACGACGCTTGGTTT EDGYDAWFHCzu18 ACC [SEQ TCTGCAACTACAACGAGAAGTT FKS GCTTAC AY [SEQ ID NO: ID NO:CAAGTCC [SEQ ID NO: [SEQ ID NO: 705] [SEQ ID 701] 702] [SEQ ID NO: 703]704] NO: 706] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCADIYPGSSICNYADK GAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu19 ACC [SEQTCTGCAACTACGCCGACAAGTT FKG GCTTAC AY [SEQ ID NO: ID NO: CAAGGGC[SEQ ID NO: [SEQ ID NO: 711] [SEQ ID 7071 708] [SEQ ID NO: 709] 710]NO: 712] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCA DIYPGSSICNYADKGAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu20 ACC [SEQ TCTGCAACTACGCCGACAAGTTFKG GCTTAC AY [SEQ ID NO: ID NO: CAAGGGC [SEQ ID NO: [SEQ ID NO: 717][SEQ ID 713] 714] [SEQ ID NO: 715] 716] NO: 718] 7G6- ACCTACTGGATC TYWITGACATCTACCCCGGCTCCTCCA DIYPGSSISNYADS GAGGACGGCTACGACGCTTGGTTT EDGYDAWFHCzu23 ACC [SEQ TCTCCAACTACGCCGACTCCGT VKG GCCTAC AY [SEQ ID NO: ID NO:CAAGGGC [SEQ ID NO: [SEQ ID NO: 723] [SEQ ID 719] 720] [SEQ ID NO: 721]722] NO: 724] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCADIYPGSSISNYNEK GAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu24 ACC [SEQTCTCCAACTACAACGAGAAGTT FKS GCCTAC AY [SEQ ID NO: ID NO: CAAGTCC[SEQ ID NO: [SEQ ID NO: 729] [SEQ ID 725] 726] [SEQ ID NO: 727 728]NO: 730] 7G6- ACCTACTGGATC TYWIT GACATCTACCCCGGCTCCTCCA DIYPGSSISNYNEKGAGGACGGCTACGACGCTTGGTTT EDGYDAWF HCzu25 ACC SEQ TCTCCAACTACAACGAGAAGTTFKS GCTTAC AY [SEQ ID NO: ID NO: CAAGTCC [SEQ ID [SEQ ID NO: 735][SEQ ID 731] 732] [SEQ ID NO: 733] NO: 734] NO: 736]7G6 VL numbered according to Kabat Clone Name (Species VL CDR1 VL CDR2VL CDR3 & VL CDR1 Amino Acid VL CDR2 Amino Acid VL CDR3 Amino AcidIsotype) DNA Sequence Sequence DNA Sequence Sequence DNA SequenceSequence mouse AGATCTAGTCAGAGCATTTTA RSSQSILHSNGNT AAAGTTTCCAACCGKVSNRFS TTTCAAGGTTCACATGTTCCAT FQGSHVP 7G6-V_(K) CATAGTAATGGAAACACCTATYLE ATTTTCT [SEQ ID TCACG FT TTAGAA [SEQ ID NO: [SEQ ID NO: NO:[SEQ ID NO: 741] [SEQ ID [SEQ ID NO: 737] 738] 739] 740] NO: 742] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu1 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: [SEQ ID NO: NO:[SEQ ID NO: 747] [SEQ ID 743] 744] 745] 746] NO: 748] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu2 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 753][SEQ ID [SEQ ID NO: 749] 750] 751] 752] NO: 754] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu3 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 759][SEQ ID [SEQ ID NO: 755] 756] 757] 758] NO: 760] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu4 CACTCCAACGGCAACACCTAC YLE GTTCTCT[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 765][SEQ ID [SEQ ID NO: 761] 762] 763] 764] NO: 766] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu5 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 771][SEQ ID [SEQ ID NO: 767] 768] 769] 770] NO: 772] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu6 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 777][SEQ ID [SEQ ID NO: 773] 774] 775] 776] NO: 778] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu7 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 783][SEQ ID [SEQ ID NO: 779] 780] 781] 782] NO: 784] 7G6-AGATCCTCCCAGTCCATCGTG RSSQSIVHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu8 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 789][SEQ ID [SEQ ID NO: 785] 786] 787] 788] NO: 790] 7G6-AGATCCTCCCAGTCCATCGTG RSSQSIVHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu9 CACTCCAACGGCAACACCTAC YLN GTTCTCC[SEQ ID TCACC FT CTGAAC [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 795][SEQ ID [SEQ ID NO: 791] 792] 793] 794 NO: 796] 7G6-AGATCCTCCCAGTCCATCGTG RSSQSIVHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu10 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: 800][SEQ ID NO: 801] [SEQ ID [SEQ ID NO: 797] 798] 799] NO: 802] 7G6-CGGTCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu11 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 807][SEQ ID [SEQ ID NO: 803] 804] 805] 806] NO: 808] 7G6-CGGTCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu12 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 813][SEQ ID [SEQ ID NO: 809] 810] 811] 812] NO: 814] 7G6-CGGTCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu13 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 819][SEQ ID [SEQ ID NO: 815] 816] 817] 818] NO: 820] 7G6-CGGTCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu14 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 825][SEQ ID [SEQ ID NO: 821] 822] 823] 824] NO: 826] 7G6-CGGTCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu15 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 831][SEQ ID [SEQ ID NO: 827] 828] 829] 830] NO: 832] 7G6-CGGTCCTCCCAGTCCATCGTG RSSQSIVHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu16 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 837][SEQ ID [SEQ ID NO: 833] 834] 835] 836] NO: 838] 7G6-CGGTCCTCCCAGTCCATCGTG RSSQSIVHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu17 CACTCCAACGGCAACACCTAC YLN GTTCTCC[SEQ ID TCACC FT CTGAAC [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 843][SEQ ID [SEQ ID NO: 839] 840] 841] 842] NO: 844] 7G6-CGGTCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu18 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 849][SEQ ID [SEQ ID NO: 845] 846] 847] 848] NO: 850] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu21 CACTCCAACGGCAACACCTAC YLE GTTCTCC[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 855][SEQ ID [SEQ ID NO: 851] 852] 853] 854] NO: 856] 7G6-AGATCCTCCCAGTCCATCCTG RSSQSILHSNGNT AAGGTGTCCAACCG KVSNRFSTTTCAAGGCTCCCACGTGCCCT FQGSHVP LCzu22 CACTCCAACGGCAACACCTAC YLE GTTCTCT[SEQ ID TCACC FT CTGGAA [SEQ ID NO: [SEQ ID NO: NO: [SEQ ID NO: 861][SEQ ID [SEQ ID NO: 857] 858] 859] 860] NO: 862]7G6 VH numbered according to IMGT Clone Name (Species VH CDR1 VH CDR2VH CDR3 & VH CDR1 Amino Acid VH CDR2 Amino Acid VH CDR3 Amino AcidIsotype) DNA Sequence Sequence DNA Sequence Sequence DNA SequenceSequence mouse GGCTACACCTTCA GYTFTTY ATTTATCCTGGTAGTAGTATTT IYPGSSIGCAAGGGAGGATGGTTACGACGCCTG AREDGYDAWFAY 7G6-Vh CCACCTACTGG W GT CGTTTGCTTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 865] [SEQ ID[SEQ ID NO: 867] 868] 863] NO: NO: 864] 866] 7G6- GGCTACACCTTTA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAYHCzu1 CCACCTACTGG W GC C GTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 871] [SEQ ID [SEQ ID NO: 873] 874] 869] NO: NO: 870] 872]7G6- GGCTACACCTTTA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu2 CCACCTACTGG W GC CGTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 877] [SEQ ID[SEQ ID NO: 879] 880] 875] NO: NO: 876] 878] 7G6- GGCTACACCTTTA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAYHCzu3 CCACCTACTGG W GC C GTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 883] [SEQ ID [SEQ ID NO: 885] 886] 881] NO: 882] NO: 884]7G6- GGCTACACCTTTA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu4 CCACCTACTGG W GC CGTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 889] [SEQ ID[SEQ ID NO: 891] 892] 887] NO: NO: 888] 890] 7G6- GGCTACACCTTTA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAYHCzu5 CCACCTACTGG W CC S GTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 895] [SEQ ID [SEQ ID NO: 897] 898] 893] NO: 894] NO: 896]7G6- GGCTACACCTTTA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu6 CCACCTACTGG W CC SGTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 901] [SEQ ID[SEQ ID NO: 903] 904] 899] NO: NO: 902] 900] 7G6- GGCTACACCTTTA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAYHCzu7 CCACCTACTGG W CC S GTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 907] [SEQ ID [SEQ ID NO: 909] 910] 905] NO: NO: 908] 906]7G6- GGCTACACCTTTA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu8 CCACCTACTGG W CC SGTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 913] [SEQ ID[SEQ ID NO: 915] 916] 911] NO: NO: 914] 912] 7G6- GGCTACACCTTTA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAYHCzu9 CCACCTACTGG W GC C GTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 919] [SEQ ID [SEQ ID NO: 921] 922] 917] NO: NO: 918] 920]7G6- GGCTACACCTTTA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu10 CCACCTACTGG W GC CGTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 925] [SEQ ID[SEQ ID NO: 927] 928] 923] NO: NO 924] 926] 7G6- GGCTACACCTTCA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCCAAAGAGGACGGCTACGACGCTTG AKEDGYDAWFAYHCzu11 CCACCTACTGG W GC C GTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 931] [SEQ ID [SEQ ID NO: 933] 934] 929] NO: 930] NO: 932]7G6- GGCTACACCTTCA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCCAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu12 CCACCTACTGG W GC CGTTTGCTTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 937] [SEQ ID[SEQ ID NO: 939] 940] 935] NO: 936] NO: 938] 7G6- GGCTACACCTTCA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCCAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAYHCzu13 CCACCTACTGG W GC C GTTTGCTTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 943] [SEQ ID [SEQ ID NO: 945] 946] 941] NO: 942] NO: 944]7G6- GGCTACACCTTCA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCCAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu14 CCACCTACTGG W GC CGTTTGCTTAC [SEQ ID [SEQ ID [SEQ ID [SEQ ID NO: 949] [SEQ ID[SEQ ID NO: 951] NO: 952] NO: 947] NO: NO: 948] 950] 7G6- GGCTACACCTTCAGYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSI GCCAGAGAGGACGGCTACGACGCTTGAREDGYDAWFAY HCzu15 CCACCTACTGG W GC C GTTTGCTTAC [SEQ ID [SEQ ID[SEQ ID [SEQ ID NO: 955] [SEQ ID [SEQ ID NO: 957] NO: 958] NO: 953]NO: 954] NO: 956] 7G6- GGCTACACCTTCA GYTFTTY ATCTACCCCGGCTCCTCCATCTIYPGSSI GCCAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu16 CCACCTACTGG W GCC GTTTGCTTAC [SEQ ID [SEQ ID NO: [SEQ ID [SEQ ID NO: 961] [SEQ ID[SEQ ID NO: 963] NO: 964] 959] NO: NO: 960] 962] 7G6- GGCTACACCTTCAGYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSI GCCAGAGAGGACGGCTACGACGCTTGAREDGYDAWFAY HCzu17 CCACCTACTGG W GC C GTTTGCTTAC [SEQ ID [SEQ ID NO:[SEQ ID [SEQ ID NO: 967] [SEQ ID [SEQ ID NO: 969] NO:970] 965] NO: NO:966] 968] 7G6- GGCTACACCTTCA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCCAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu18 CCACCTACTGG W GC CGTTTGCTTAC [SEQ ID [SEQ ID NO: [SEQ ID [SEQ ID NO: 973] [SEQ ID[SEQ ID NO: 975] NO: 976] 971] NO: NO: 972] 974] 7G6- GGCTACACCTTCAGYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSI GCCAGAGAGGACGGCTACGACGCTTGAREDGYDAWFAY HCzu19 CCACCTACTGG W GC C GTTTGCTTAC [SEQ ID NO: [SEQ ID[SEQ ID [SEQ ID NO: 979] [SEQ ID [SEQ ID NO: 981] 982] NO: 977] NO: 978]NO: 980] 7G6- GGCTACACCTTCA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCCAAAGAGGACGGCTACGACGCTTG AKEDGYDAWFAY HCzu20 CCACCTACTGG W GC CGTTTGCTTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 985] [SEQ ID[SEQ ID NO: 987] 988] 983] NO: 984] NO: 986] 7G6- GGCTACACCTTCA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCTAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAYHCzu23 CCACCTACTGG W CC S GTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 991] [SEQ ID [SEQ ID NO: 993] 994] 989] NO: NO: 990] 992]7G6- GGCTACACCTTCA GYTFTTY ATCTACCCCGGCTCCTCCATCT IYPGSSIGCCAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAY HCzu24 CCACCTACTGG W CC SGTTTGCCTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID [SEQ ID NO: 997] [SEQ ID[SEQ ID NO: 999] 1000] 995] NO: NO: 996] 998] 7G6- GGCTACACCTTCA GYTFTTYATCTACCCCGGCTCCTCCATCT IYPGSSI GCCAGAGAGGACGGCTACGACGCTTG AREDGYDAWFAYHCzu25 CCACCTACTGG W CC S GTTTGCTTAC [SEQ ID NO: [SEQ ID NO: [SEQ ID[SEQ ID NO: 1003] [SEQ ID [SEQ ID NO: 1005] 1006] 1001] NO: NO: 1002]1004] 7G6 VL numbered according to IMGT Clone Name (Species VL CDR1VL CDR2 VL CDR3 & VL CDR1 Amino Acid VL CDR2 Amino Acid VL CDR3Amino Acid Isotype) DNA Sequence Sequence DNA Sequence SequenceDNA Sequence Sequence mouse CAGAGCATTTTACATAGTAATGGAAACACC QSILHSNGNTAAAGTTTC KVS TTTCAAGGTTCACATGTTCCATTC FQGSHVPF 7G6-V_(K) TAT Y C [SEQ IDACG T [SEQ ID NO: 1007] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1011] [SEQ IDNO: 1008] NO: 1010] NO: 1009] 1012] 7G6- CAGTCCATCCTGCACTCCAACGGCAACACCQSILHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu1 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1013] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1017][SEQ ID NO: 1014] NO: 1016] NO: 1015] 1018] 7G6-CAGTCCATCCTGCACTCCAACGGCAACACC QSILHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu2 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1019] [SEQ ID [SEQ ID NO: [SEQ ID NO:1023] [SEQ ID NO: 1020]NO: 1022] NO: 1021] 1024] 7G6- CAGTCCATCCTGCACTCCAACGGCAACACC QSILHSNGNTAAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu3 TAC Y C [SEQ ID ACCT [SEQ ID NO: 1025] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1029] [SEQ IDNO: 1026] NO: 1028] NO:1030] 1027] 7G6- CAGTCCATCCTGCACTCCAACGGCAACACCQSILHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu4 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1031] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1035][SEQ ID NO: 1032] NO: 1034] NO: 1033] 1036] 7G6-CAGTCCATCCTGCACTCCAACGGCAACACC QSILHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu5 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1037] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1041] [SEQ IDNO: 1038] NO: 1040] NO: 1039] 1042] 7G6- CAGTCCATCCTGCACTCCAACGGCAACACCQSILHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu6 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1043] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1047][SEQ ID NO: 1044] NO: 1046] NO: 1045] 1048] 7G6-CAGTCCATCCTGCACTCCAACGGCAACACC QSILHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu7 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1049] [SEQ ID [SEQ ID NO: 1052] [SEQ ID NO: 1053] [SEQ IDNO: 1050] NO: NO: 1051] 1054] 7G6- CAGTCCATCGTGCACTCCAACGGCAACACCQSIVHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu8 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1055] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1059][SEQ ID NO: 1056] NO: 1058] NO: 1057] 1060] 7G6-CAGTCCATCGTGCACTCCAACGGCAACACC QSIVHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu9 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1061] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1065] [SEQ IDNO: 1062] NO: 1064] NO: 1063] 1066] 7G6- CAGTCCATCGTGCACTCCAACGGCAACACCQSIVHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu10 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1067] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1071][SEQ ID NO: 1068] NO: 1070] NO: 1069] 1072] 7G6-CAGTCCATCCTGCACTCCAACGGCAACACC QSILHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu11 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1073] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1077] [SEQ IDNO: 1074] NO: 1076] NO: 1075] 1078] 7G6- CAGTCCATCCTGCACTCCAACGGCAACACCQSILHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu12 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1079] [SEQ ID [SEQ ID NO: 1082][SEQ ID NO: 1083] [SEQ ID NO: 1080] NO: NO: 1081] 1084] 7G6-CAGTCCATCCTGCACTCCAACGGCAACACC QSILHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu13 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1085] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1089] [SEQ IDNO: 1086] NO: 1088] NO: 1087] 1090] 7G6- CAGTCCATCCTGCACTCCAACGGCAACACCQSILHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu14 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1091] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1095][SEQ ID NO: 1092] NO: 1094] NO: 1093] 1096] 7G6-CAGTCCATCCTGCACTCCAACGGCAACACC QSILHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu15 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1097] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1101] [SEQ IDNO: 1098] NO: 1100] NO: 1099] 1102] 7G6- CAGTCCATCGTGCACTCCAACGGCAACACCQSIVHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu16 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1103] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1107][SEQ ID NO: 1104] NO: 1106] NO: 1105] 1108] 7G6-CAGTCCATCGTGCACTCCAACGGCAACACC QSIVHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu17 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1109] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1113] [SEQ IDNO: 1110] NO: 1112] NO: 1111] 1114] 7G6- CAGTCCATCCTGCACTCCAACGGCAACACCQSILHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu18 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1115] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1119][SEQ ID NO: 1116] NO: 1118] NO: 1117] 1120] 7G6-CAGTCCATCCTGCACTCCAACGGCAACACC QSILHSNGNT AAGGTGTC KVSTTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu21 TAC Y C [SEQ ID ACC T[SEQ ID NO: 1121] [SEQ ID [SEQ ID NO: [SEQ ID NO: 1125] [SEQ IDNO: 1122] NO: 1124] NO: 1123] 1126] 7G6- CAGTCCATCCTGCACTCCAACGGCAACACCQSILHSNGNT AAGGTGTC KVS TTTCAAGGCTCCCACGTGCCCTTC FQGSHVPF LCzu22 TAC Y C[SEQ ID ACC T [SEQ ID NO: 1127] [SEQ ID [SEQ ID NO: 1130][SEQ ID NO: 1131] [SEQ ID NO: 1128] NO: NO: 1129] 1132]

In some embodiments, the anti-Tau antibodies, or antigen-bindingfragments thereof, include a heavy chain complementarity determiningregion 1 (HCDR1), a heavy chain complementarity determining region 2(HCDR2), and a heavy chain complementarity determining region 3 (HCDR3)as set forth in SEQ ID NO: 196 and a light chain complementaritydetermining region 1 (LCDR1), a light chain complementarity determiningregion 2 (LCDR2), and a light chain complementarity determining region 3(LCDR3) as set forth in SEQ ID NO: 411. In some embodiments, theanti-Tau antibodies, or antigen-binding fragments thereof, include aHCDR1, a HCDR2, and a HCDR3 as set forth in SEQ ID NO: 268 and a LCDR1,a LCDR2, and a LCDR3 as set forth in SEQ ID NO: 465. In someembodiments, the anti-Tau antibodies, or antigen-binding fragmentsthereof, include a HCDR1, a HCDR2, and a HCDR3 as set forth in SEQ IDNO: 402 and a LCDR1, a LCDR2, and a LCDR3 as set forth in SEQ ID NO:572.

In some embodiments, the anti-Tau antibodies or antigen-bindingfragments may include a light chain CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 738, as definedaccording to the method of Kabat. In some embodiments, antibodies orantigen-binding fragments may include a light chain CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 740, asdefined according to the method of Kabat. In some embodiments,antibodies or antigen-binding fragments may include a light chain CDR3amino acid sequence substantially the same as, or identical to, SEQ IDNO: 742, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR1 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 594, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR2 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 596, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR3 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 598, as defined according to the method of Kabat. Theantibodies or antigen-binding fragments may include a light chain havinga CDR1 amino acid sequence substantially the same as, or identical to,SEQ ID NO: 738, as defined according to the method of Kabat; a CDR2amino acid sequence substantially the same as, or identical to, SEQ IDNO: 740, as defined according to the method of Kabat; and a CDR3 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:742, as defined according to the method of Kabat. The antibodies orantigen-binding fragments may include a heavy chain having a CDR1 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:594, as defined according to the method of Kabat; a CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 596, asdefined according to the method of Kabat; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 598, as definedaccording to the method of Kabat. The antibodies or antigen-bindingfragments may include a light chain having a CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 738, as definedaccording to the method of Kabat; a CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 740, as definedaccording to the method of Kabat; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 742, as definedaccording to the method of Kabat, and also have a heavy chain having aCDR1 amino acid sequence substantially the same as, or identical to, SEQID NO: 594, as defined according to the method of Kabat; a CDR2 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:596, as defined according to the method of Kabat; and a CDR3 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 598, asdefined according to the method of Kabat.

In some embodiments, the anti-Tau antibodies or antigen-bindingfragments may include a light chain CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1008, as definedby IMGT. In some embodiments, antibodies or antigen-binding fragmentsmay include a light chain CDR2 amino acid sequence substantially thesame as, or identical to, SEQ ID NO: 1010, as defined by IMGT. In someembodiments, antibodies or antigen-binding fragments may include a lightchain CDR3 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 1012, as defined by IMGT. In some embodiments, antibodiesor antigen-binding fragments may include a heavy chain CDR1 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 864, asdefined by IMGT. In some embodiments, antibodies or antigen-bindingfragments may include a heavy chain CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 866, as definedby IMGT. In some embodiments, antibodies or antigen-binding fragmentsmay include a heavy chain CDR3 amino acid sequence substantially thesame as, or identical to, SEQ ID NO: 868, as defined by IMGT. Theantibodies or antigen-binding fragments may include a light chain havinga CDR1 amino acid sequence substantially the same as, or identical to,SEQ ID NO: 1008, as defined by IMGT; a CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1010, as definedby IMGT; and a CDR3 amino acid sequence substantially the same as, oridentical to, SEQ ID NO: 1012, as defined by IMGT. The antibodies orantigen-binding fragments may include a heavy chain having a CDR1 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:864, as defined by IMGT; a CDR2 amino acid sequence substantially thesame as, or identical to, SEQ ID NO: 866, as defined by IMGT; and a CDR3amino acid sequence substantially the same as, or identical to, SEQ IDNO: 868, as defined by IMGT. The antibodies or antigen-binding fragmentsmay include a light chain having a CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1008, as definedby IMGT; a CDR2 amino acid sequence substantially the same as, oridentical to, SEQ ID NO: 1010, as defined by IMGT; and a CDR3 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 1012, asdefined by IMGT, and also have a heavy chain having a CDR1 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 864, asdefined by IMGT; a CDR2 amino acid sequence substantially the same as,or identical to, SEQ ID NO: 866, as defined by IMGT; and a CDR3 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:868, as defined by IMGT.

In some embodiments, the anti-Tau antibodies or antigen-bindingfragments may include a light chain CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 774, as definedaccording to the method of Kabat. In some embodiments, antibodies orantigen-binding fragments may include a light chain CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 776, asdefined according to the method of Kabat. In some embodiments,antibodies or antigen-binding fragments may include a light chain CDR3amino acid sequence substantially the same as, or identical to, SEQ IDNO: 778, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR1 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 642, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR2 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 644, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR3 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 646, as defined according to the method of Kabat. Theantibodies or antigen-binding fragments may include a light chain havinga CDR1 amino acid sequence substantially the same as, or identical to,SEQ ID NO: 774, as defined according to the method of Kabat; a CDR2amino acid sequence substantially the same as, or identical to, SEQ IDNO: 776, as defined according to the method of Kabat; and a CDR3 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:778, as defined according to the method of Kabat. The antibodies orantigen-binding fragments may include a heavy chain having a CDR1 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:642, as defined according to the method of Kabat; a CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 644, asdefined according to the method of Kabat; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 646, as definedaccording to the method of Kabat. The antibodies or antigen-bindingfragments may include a light chain having a CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 774, as definedaccording to the method of Kabat; a CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 776, as definedaccording to the method of Kabat; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 778, as definedaccording to the method of Kabat, and also have a heavy chain having aCDR1 amino acid sequence substantially the same as, or identical to, SEQID NO: 642, as defined according to the method of Kabat; a CDR2 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:644, as defined according to the method of Kabat; and a CDR3 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 646, asdefined according to the method of Kabat.

In some embodiments, the anti-Tau antibodies or antigen-bindingfragments may include a light chain CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1044, as definedaccording to the method of IMGT. In some embodiments, antibodies orantigen-binding fragments may include a light chain CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 1046, asdefined according to the method of IMGT. In some embodiments, antibodiesor antigen-binding fragments may include a light chain CDR3 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 1048, asdefined according to the method of IMGT. In some embodiments, antibodiesor antigen-binding fragments may include a heavy chain CDR1 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 912, asdefined according to the method of IMGT. In some embodiments, antibodiesor antigen-binding fragments may include a heavy chain CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 914, asdefined according to the method of IMGT. In some embodiments, antibodiesor antigen-binding fragments may include a heavy chain CDR3 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 916, asdefined according to the method of IMGT. The antibodies orantigen-binding fragments may include a light chain having a CDR1 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:1044, as defined according to the method of IMGT; a CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 1046, asdefined according to the method of IMGT; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1048, as definedaccording to the method of IMGT. The antibodies or antigen-bindingfragments may include a heavy chain having a CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 912, as definedaccording to the method of IMGT; a CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 914, as definedaccording to the method of IMGT; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 916, as definedaccording to the method of IMGT. The antibodies or antigen-bindingfragments may include a light chain having a CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1044, as definedaccording to the method of IMGT; a CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1046, as definedaccording to the method of IMGT; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1048, as definedaccording to the method of IMGT, and also have a heavy chain having aCDR1 amino acid sequence substantially the same as, or identical to, SEQID NO: 912, as defined according to the method of IMGT; a CDR2 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:914, as defined according to the method of IMGT; and a CDR3 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 916, asdefined according to the method of IMGT.

In some embodiments, the anti-Tau antibodies or antigen-bindingfragments may include a light chain CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 846, as definedaccording to the method of Kabat. In some embodiments, antibodies orantigen-binding fragments may include a light chain CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 848, asdefined according to the method of Kabat. In some embodiments,antibodies or antigen-binding fragments may include a light chain CDR3amino acid sequence substantially the same as, or identical to, SEQ IDNO: 850, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR1 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 732, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR2 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 734, as defined according to the method of Kabat. In someembodiments, antibodies or antigen-binding fragments may include a heavychain CDR3 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 736, as defined according to the method of Kabat. Theantibodies or antigen-binding fragments may include a light chain havinga CDR1 amino acid sequence substantially the same as, or identical to,SEQ ID NO: 846, as defined according to the method of Kabat; a CDR2amino acid sequence substantially the same as, or identical to, SEQ IDNO: 848, as defined according to the method of Kabat; and a CDR3 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:850, as defined according to the method of Kabat. The antibodies orantigen-binding fragments may include a heavy chain having a CDR1 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:732, as defined according to the method of Kabat; a CDR2 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 734, asdefined according to the method of Kabat; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 736, as definedaccording to the method of Kabat. The antibodies or antigen-bindingfragments may include a light chain having a CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 846, as definedaccording to the method of Kabat; a CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 848, as definedaccording to the method of Kabat; and a CDR3 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 850, as definedaccording to the method of Kabat, and also have a heavy chain having aCDR1 amino acid sequence substantially the same as, or identical to, SEQID NO: 732, as defined according to the method of Kabat; a CDR2 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:734, as defined according to the method of Kabat; and a CDR3 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 736, asdefined according to the method of Kabat.

In some embodiments, the anti-Tau antibodies or antigen-bindingfragments may include a light chain CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1116, as definedby IMGT. In some embodiments, antibodies or antigen-binding fragmentsmay include a light chain CDR2 amino acid sequence substantially thesame as, or identical to, SEQ ID NO: 1118, as defined by IMGT. In someembodiments, antibodies or antigen-binding fragments may include a lightchain CDR3 amino acid sequence substantially the same as, or identicalto, SEQ ID NO: 1120, as defined by IMGT. In some embodiments, antibodiesor antigen-binding fragments may include a heavy chain CDR1 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 1002, asdefined by IMGT. In some embodiments, antibodies or antigen-bindingfragments may include a heavy chain CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1004, as definedby IMGT. In some embodiments, antibodies or antigen-binding fragmentsmay include a heavy chain CDR3 amino acid sequence substantially thesame as, or identical to, SEQ ID NO: 1006, as defined by IMGT. Theantibodies or antigen-binding fragments may include a light chain havinga CDR1 amino acid sequence substantially the same as, or identical to,SEQ ID NO: 1116, as defined by IMGT; a CDR2 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1118, as definedby IMGT; and a CDR3 amino acid sequence substantially the same as, oridentical to, SEQ ID NO: 1120, as defined by IMGT. The antibodies orantigen-binding fragments may include a heavy chain having a CDR1 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:1002, as defined by IMGT; a CDR2 amino acid sequence substantially thesame as, or identical to, SEQ ID NO: 1004, as defined by IMGT; and aCDR3 amino acid sequence substantially the same as, or identical to, SEQID NO: 1006, as defined by IMGT. The antibodies or antigen-bindingfragments may include a light chain having a CDR1 amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 1116, as definedby IMGT; a CDR2 amino acid sequence substantially the same as, oridentical to, SEQ ID NO: 1118, as defined by IMGT; and a CDR3 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 1120, asdefined by IMGT, and also have a heavy chain having a CDR1 amino acidsequence substantially the same as, or identical to, SEQ ID NO: 1002, asdefined by IMGT; a CDR2 amino acid sequence substantially the same as,or identical to, SEQ ID NO: 1004, as defined by IMGT; and a CDR3 aminoacid sequence substantially the same as, or identical to, SEQ ID NO:1006, as defined by IMGT.

Antigen-binding arrangements of CDRs may also be engineered usingantibody-like proteins as CDR scaffolding. Such engineeredantigen-binding proteins are within the scope of the disclosure.

In some embodiments of the antibodies or antigen-binding fragments thatspecifically bind Tau described herein, certain residues are altered toimprove the binding and/or folding characteristics of the antibody orantigen-binding fragment. For example, in some embodiments of thedisclosed monoclonal antibodies and antigen-binding fragments, theresidue at position 49 of the light chain according to the method ofKabat is not cysteine. In some embodiments of the disclosed monoclonalantibodies and antigen-binding fragments, the residue at position 49 ofthe light chain according to the method of Kabat is serine. In someembodiments of the antibodies or antigen-binding fragments thatspecifically bind Tau described herein, the residue at position 57 ofthe heavy chain according to the method of Kabat is not cysteine. Insome embodiments, the residue at position 57 of the heavy chainaccording to the method of Kabat is serine. In some embodiments of theantibodies or antigen-binding fragments that specifically bind Taudescribed herein, the residue at position 34 of the light chainaccording to the method of Kabat is glutamate. In some embodiments ofthe antibodies or antigen-binding fragments that specifically bind Taudescribed herein, the residue at position 36 of the light chainaccording to the method of Kabat is not phenylalanine. The residue atposition 36 of the light chain according to the method of Kabat may betyrosine. In some embodiments of the antibodies or antigen-bindingfragments that specifically bind Tau described herein, the residue atposition 46 of the light chain according to the method of Kabat is notarginine. The residue at position 46 of the light chain according to themethod of Kabat may be leucine. In some embodiments of the antibodies orantigen-binding fragments that specifically bind Tau described herein,the residue at position 94 of the heavy chain according to the method ofKabat is not lysine. In some embodiments of the antibodies orantigen-binding fragments that specifically bind Tau described herein,the residue at position 71 of the heavy chain according to the method ofKabat is not arginine. The residue at position 71 of the heavy chainaccording to the method of Kabat may be valine.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 411. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 411 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 410may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:196. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 196 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 195 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 411, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 196. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 411 and asequence substantially the same as, or identical to, SEQ ID NO: 196 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 410 anda sequence substantially the same as, or identical to, SEQ ID NO: 195 isprovided.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 465. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 465 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 464may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:268. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 268 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 267 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 465, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 268. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 465 and asequence substantially the same as, or identical to, SEQ ID NO: 268 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 464 anda sequence substantially the same as, or identical to, SEQ ID NO: 267 isprovided.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 581. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 581 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 580may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:268. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 268 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 267 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 581, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 268. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 581 and asequence substantially the same as, or identical to, SEQ ID NO: 268 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 580 anda sequence substantially the same as, or identical to, SEQ ID NO: 267 isprovided.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 545. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 545 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 544may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:384. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 384 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 383 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 545, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 384. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 545 and asequence substantially the same as, or identical to, SEQ ID NO: 384 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 544 anda sequence substantially the same as, or identical to, SEQ ID NO: 383 isprovided.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 545. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 545 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 544may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:393. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 393 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 392 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 545, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 393. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 545 and asequence substantially the same as, or identical to, SEQ ID NO: 393 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 544 anda sequence substantially the same as, or identical to, SEQ ID NO: 392 isprovided.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 545. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 545 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 544may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:402. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 402 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 401 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 545, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 402. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 545 and asequence substantially the same as, or identical to, SEQ ID NO: 402 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 544 anda sequence substantially the same as, or identical to, SEQ ID NO: 401 isprovided.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 572. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 572 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 571may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:384. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 384 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 383 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 572, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 384. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 572 and asequence substantially the same as, or identical to, SEQ ID NO: 384 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 571 anda sequence substantially the same as, or identical to, SEQ ID NO: 383 isprovided.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 572. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 572 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 571may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:393. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 393 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 392 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 572, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 393. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 572 and asequence substantially the same as, or identical to, SEQ ID NO: 393 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 571 anda sequence substantially the same as, or identical to, SEQ ID NO: 392 isprovided.

The described antibodies or antigen-binding fragments that specificallybind Tau may include a light chain variable domain that includes anamino acid sequence substantially the same as, or identical to, SEQ IDNO: 572. In some aspects, an isolated polynucleotide that encodes asequence substantially the same as, or identical to, SEQ ID NO: 572 isprovided. In some embodiments, an isolated polynucleotide that includesa sequence substantially the same as, or identical to, SEQ ID NO: 571may encode this light chain variable domain amino acid sequence. Thedescribed antibodies or antigen-binding fragments that specifically bindTau may include a heavy chain variable domain that includes an aminoacid sequence substantially the same as, or identical to, SEQ ID NO:402. In some aspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 402 is provided.In some embodiments, an isolated polynucleotide that includes a sequencesubstantially the same as, or identical to, SEQ ID NO: 401 may encodethis heavy chain variable domain amino acid sequence. The describedantibodies or antigen-binding fragments that specifically bind Tau mayinclude a light chain variable domain and a heavy chain variable domain,wherein the light chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 572, and theheavy chain variable domain includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 402. In someaspects, an isolated polynucleotide that encodes a sequencesubstantially the same as, or identical to, SEQ ID NO: 572 and asequence substantially the same as, or identical to, SEQ ID NO: 402 isprovided. In some embodiments an isolated polynucleotide that includes asequence substantially the same as, or identical to, SEQ ID NO: 571 anda sequence substantially the same as, or identical to, SEQ ID NO: 401 isprovided.

In some embodiments, the antibodies that specifically bind Tau areproduced by antibody-producing cells deposited with the American TypeCulture Collection (10801 University Blvd., Manassas, Virginia20110-2209) on Oct. 11, 2017 and have been assigned Accession No.PTA-124523 or PTA-124524. In some embodiments, the antibodies, orantigen-binding fragments thereof, have the binding affinity formonomeric wild-type 2N4R Tau of the antibodies produced by the depositedantibody-producing cells as measured by surface plasmon resonance. Insome embodiments, the disclosed antibodies, or antigen-binding fragmentsthereof, comprise the light and heavy chain CDRs of the antibodiesproduced by the deposited antibody-producing cells. In some embodiments,the antibodies, or antigen-binding fragments thereof, comprise the lightand heavy chain variable regions of the antibodies produced by thedeposited antibody-producing cells.

The antibodies or antigen-binding fragments that specifically bind Taudescribed herein include variants having single or multiple amino acidsubstitutions, deletions, or additions that retain the biologicalproperties (e.g., binding affinity or immune effector activity) of thedescribed antibodies or antigen-binding fragments. The skilled personmay produce variants having single or multiple amino acid substitutions,deletions, or additions. These variants may include: (a) variants inwhich one or more amino acid residues are substituted with conservativeor nonconservative amino acids, (b) variants in which one or more aminoacids are added to or deleted from the polypeptide, (c) variants inwhich one or more amino acids include a substituent group, and (d)variants in which the polypeptide is fused with another peptide orpolypeptide such as a fusion partner, a protein tag or other chemicalmoiety, that may confer useful properties to the polypeptide, such as,for example, an epitope for an antibody, a polyhistidine sequence, abiotin moiety and the like. Antibodies or antigen-binding fragmentsdescribed herein may include variants in which amino acid residues fromone species are substituted for the corresponding residue in anotherspecies, either at the conserved or nonconserved positions. In otherembodiments, amino acid residues at nonconserved positions aresubstituted with conservative or nonconservative residues. Thetechniques for obtaining these variants, including genetic(suppressions, deletions, mutations, etc.), chemical, and enzymatictechniques, are known to the person having ordinary skill in the art.

The antibodies or antigen-binding fragments described herein havebinding affinities (in nM) for wild-type monomeric 2N4R Tau that includea dissociation constant (K_(D)) of less than about 1×10⁻⁸ M as measuredby surface plasmon resonance. In certain embodiments, the antibodies orantigen-binding fragments described herein have binding affinities (innM) for wild-type monomeric 2N4R Tau that include a dissociationconstant (K_(D)) of less than about 0.5 nM as measured by surfaceplasmon resonance. In certain embodiments, the antibodies orantigen-binding fragments described herein have binding affinities (innM) for wild-type monomeric 2N4R Tau that include a dissociationconstant (K_(D)) of less than about 0.3 nM as measured by surfaceplasmon resonance. In certain embodiments, the antibodies orantigen-binding fragments described herein have binding affinities (innM) for wild-type monomeric 2N4R Tau that include a dissociationconstant (K_(D)) of less than about 0.2 nM as measured by surfaceplasmon resonance. In certain embodiments, the antibodies orantigen-binding fragments described herein have binding affinities (innM) for wild-type monomeric 2N4R Tau that include a dissociationconstant (K_(D)) of less than about 0.15 nM as measured by surfaceplasmon resonance. In certain embodiments, the antibodies orantigen-binding fragments described herein have binding affinities (innM) for wild-type monomeric 2N4R Tau that include a dissociationconstant (K_(D)) of less than about 0.1 nM as measured by surfaceplasmon resonance.

In any of the embodiments of the antibodies or antigen-binding fragmentsthat specifically bind Tau described herein, the antibodies orantigen-binding fragments may bind an epitope comprising HVPG (SEQ IDNO: 1133). In some embodiments, the antibodies or antigen-bindingfragments that specifically bind Tau described herein are biepitopic. Incertain aspects, the antibodies or antigen-binding fragments thatspecifically bind Tau described herein bind one or more epitopes withinTau comprising HVPG (SEQ ID NO: 1133). This sequence appears twice inhuman 2N4R Tau. The first site is in 2N4R Tau within the second repeatregion at residues 299-302 and the second site within the fourth repeatregion at residues 362-365.

In any of the embodiments of the antibodies or antigen-binding fragmentsthat specifically bind Tau described herein, the antibodies orantigen-binding fragments may bind an epitope comprising HVPGG (SEQ IDNO: 79). In some embodiments, the antibodies or antigen-bindingfragments that specifically bind Tau described herein are biepitopic. Incertain aspects, the antibodies or antigen-binding fragments thatspecifically bind Tau described herein bind one or more epitopes withinTau comprising HVPGG (SEQ ID NO: 79). This sequence appears twice inhuman 2N4R Tau. The first site is in 2N4R Tau within the second repeatregion at residues 299-303 and the second site within the fourth repeatregion at residues 362-366. In certain aspects, the antibodies orantigen-binding fragments that specifically bind Tau bind the epitopewithin Tau comprising HVPGG (SEQ ID NO: 79) within repeat region 2 orrepeat region 4 with a peptide binding preference that is at least10-fold, preferably at least 20-fold, and more preferably at least30-fold greater than binding to an epitope within Tau comprising HKPGG(SEQ ID NO: 182) within repeat region 3 as determined by a peptidebinding assay (e.g., the peptide binding assay described in Example 3).In certain aspects, the antibodies or antigen-binding fragments thatspecifically bind Tau bind the epitope within Tau comprising HVPGG (SEQID NO: 79) within repeat region 2 or repeat region 4 with a peptidebinding preference that is at least 10-fold, preferably at least20-fold, and more preferably at least 30-fold greater than binding to anepitope within Tau comprising HQPGG (SEQ ID NO: 183) within repeatregion 1, as determined by a peptide binding assay (e.g., the peptidebinding assay described in Example 3). In certain aspects, theantibodies or antigen-binding fragments that specifically bind Tau bindthe epitope within Tau comprising HVPGG (SEQ ID NO: 79) within repeatregion 2 or repeat region 4 with a peptide binding preference that is atleast 10-fold, preferably at least 20-fold, and more preferably at least30-fold greater than binding to an epitope within Tau comprising HKPGG(SEQ ID NO: 182) within repeat region 3 and that is at least 10-fold,preferably at least and more preferably at least 30-fold greater thanbinding to an epitope comprising HQPGG (SEQ ID NO: 183) within repeatregion 1, as determined by a peptide binding assay (e.g., the peptidebinding assay described in Example 3). In certain aspects, theantibodies or antigen-binding fragments that specifically bind Tau donot bind an epitope within naturally occurring mutant P301S Taucomprising HVSGG (SEQ ID NO: 184) within repeat region 2 as determinedby a peptide binding assay (e.g., the peptide binding assay described inExample 4). In certain aspects, the antibodies or antigen-bindingfragments that specifically bind Tau do not bind an epitope withinnaturally occurring mutant P301L Tau comprising HVLGG (SEQ ID NO: 185)within repeat region 2 as determined by a peptide binding assay (e.g.,the peptide binding assay described in Example 4). The amino acidsequence HVSGG (SEQ ID NO: 184) is present at residues 299-303 in the2N4R Tau sequence of P301S in vitro and in vivo Tauopathy models. Theamino acid sequence HVLGG (SEQ ID NO: 185) is present at residues299-303 of the 2N4R Tau sequence of P301L in vitro and in vivo Tauopathymodels. Antibodies or antigen-binding fragments as provided herein thatpreferably bind one or more epitopes within Tau comprising HVPGG (SEQ IDNO: 79) within repeat region 2 or repeat region 4 relative to an epitopecomprising HKPGG (SEQ ID NO: 182 within repeat region 3 or HQPGG (SEQ IDNO: 183) within repeat region 1 and do not bind an epitope comprisingHVSGG (SEQ ID NO: 184), or HVLGG (SEQ ID NO: 185) within repeat region 2bind 2N4R Tau P301S/L at residues 362-366. Surprisingly, as demonstratedherein, the described antibodies or antigen-binding fragments thatpreferably bind one or more epitopes within Tau comprising HVPGG (SEQ IDNO: 79) within repeat region 2 or repeat region 4 relative to an epitopecomprising HKPGG (SEQ ID NO: 182) within repeat region 3 or HQPGG (SEQID NO: 183) within repeat region 1 and that do not exhibit binding to anepitope comprising HVSGG (SEQ ID NO: 184) or HVLGG (SEQ ID NO: 185)within repeat region 2 reduce Tau seeding and transmission in vivo.

In certain embodiments, labelled anti-Tau antibodies are provided.Labels include, but are not limited to, labels or moieties that aredetected directly (e.g., fluorescent, chromophoric, electron-dense,chemiluminescent, and radioactive labels) and labels and moieties (e.g.,enzymes or ligands) that are detected indirectly (e.g., throughenzymatic reaction or, molecular interaction). Exemplary labels includebut are not limited to radiolabels (e.g., ³²P, ¹⁴C, ¹¹¹I, ¹²⁵I, ³H,¹³¹I), fluorescent labels (such as DyLight™ 649), epitope tags, biotin,chromophore labels, ECL labels, or enzymes. More specifically, thedescribed labels include ruthenium, DOTA,¹¹¹In-diethylenetriaminepentaacetic acid (DTPA), horseradish peroxidase,alkaline phosphatase and beta-galactosidase, poly-histidine (HIS tag),acridine dyes, cyanine dyes, fluorone dyes, oxazin dyes, phenanthridinedyes, rhodamine dyes, Alexafluor™ dyes, and the like.

Also disclosed are isolated polynucleotides that encode antibodies orantigen-binding fragments that specifically bind to Tau. In someembodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a light chain CDR1 sequencedefined according to Kabat substantially the same as, or identical to,SEQ ID NO: 738, for example SEQ ID NO: 737. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a light chain CDR2 defined according to Kabatsubstantially the same as, or identical to, SEQ ID NO: 740, for exampleSEQ ID NO: 739. In some embodiments, the isolated polynucleotides encodean antibody or antigen-binding fragment thereof having a light chainCDR3 defined according to Kabat substantially the same as, or identicalto, SEQ ID NO: 742, for example SEQ ID NO: 741. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a heavy chain CDR1 defined according to Kabatsubstantially the same as, or identical to, SEQ ID NO: 594, for exampleSEQ ID NO: 593. In some embodiments, the isolated polynucleotides encodean antibody or antigen-binding fragment thereof having a heavy chainCDR2 defined according to Kabat substantially the same as, or identicalto, SEQ ID NO: 596, for example SEQ ID NO: 595. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a heavy chain CDR3 defined according to Kabatsubstantially the same as, or identical to, SEQ ID NO: 598, for exampleSEQ ID NO: 597. The isolated polynucleotides may encode an antibody orantigen-binding fragment thereof having a light chain with a CDR1substantially the same as, or identical to, SEQ ID NO: 738, for exampleSEQ ID NO: 737; a CDR2 substantially the same as, or identical to, SEQID NO: 740, for example SEQ ID NO: 739; and a CDR3 substantially thesame as, or identical to, SEQ ID NO: 742, for example SEQ ID NO: 741,defined according to Kabat. The isolated polynucleotides may encode anantibody or antigen-binding fragment thereof having a heavy chain CDR1substantially the same as, or identical to, SEQ ID NO: 594, for exampleSEQ ID NO: 593; a CDR2 substantially the same as, or identical to, SEQID NO: 596, for example SEQ ID NO: 595; and a CDR3 substantially thesame as, or identical to, SEQ ID NO: 598, for example SEQ ID NO: 597,defined according to Kabat. The isolated polynucleotides may encode anantibody or antigen-binding fragment thereof having a light chain CDR1substantially the same as, or identical to, SEQ ID NO: 738, for exampleSEQ ID NO: 737; a CDR2 encoded by a nucleotide sequence substantiallythe same as, or identical to, SEQ ID NO: 740, for example SEQ ID NO:739; and a CDR3 encoded by a nucleotide sequence substantially the sameas, or identical to, SEQ ID NO: 742, for example SEQ ID NO: 741; and aheavy chain CDR1 substantially the same as, or identical to, SEQ ID NO:594, for example SEQ ID NO: 593; a CDR2 substantially the same as, oridentical to, SEQ ID NO: 596, for example SEQ ID NO: 595; and a CDR3substantially the same as, or identical to, SEQ ID NO: 598, for exampleSEQ ID NO: 597, defined according to Kabat.

In some embodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a light chain CDR1 sequencedefined according to IMGT substantially the same as, or identical to,SEQ ID NO: 1008, for example SEQ ID NO: 1007. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a light chain CDR2 defined according to IMGTsubstantially the same as, or identical to, SEQ ID NO: 1010, for exampleSEQ ID NO: 1009. In some embodiments, the isolated polynucleotidesencode an antibody or antigen-binding fragment thereof having a lightchain CDR3 defined according to IMGT substantially the same as, oridentical to, SEQ ID NO: 1012, for example SEQ ID NO: 1011. In someembodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a heavy chain CDR1 definedaccording to IMGT substantially the same as, or identical to, SEQ ID NO:864, for example SEQ ID NO: 863. In some embodiments, the isolatedpolynucleotides encode an antibody or antigen-binding fragment thereofhaving a heavy chain CDR2 defined according to IMGT substantially thesame as, or identical to, SEQ ID NO: 866, for example SEQ ID NO: 865. Insome embodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a heavy chain CDR3 definedaccording to IMGT substantially the same as, or identical to, SEQ ID NO:868, for example SEQ ID NO: 867. The isolated polynucleotides may encodean antibody or antigen-binding fragment thereof having a light chainwith a CDR1 substantially the same as, or identical to, SEQ ID NO: 1008,for example SEQ ID NO: 1007; a CDR2 substantially the same as, oridentical to, SEQ ID NO: 1010, for example SEQ ID NO: 1009; and a CDR3substantially the same as, or identical to, SEQ ID NO: 1012, for exampleSEQ ID NO: 1011, defined according to IMGT. The isolated polynucleotidesmay encode an antibody or antigen-binding fragment thereof having aheavy chain CDR1 substantially the same as, or identical to, SEQ ID NO:864, for example SEQ ID NO: 863; a CDR2 substantially the same as, oridentical to, SEQ ID NO: 866, for example SEQ ID NO: 865; and a CDR3substantially the same as, or identical to, SEQ ID NO: 868, for exampleSEQ ID NO: 867, defined according to IMGT. The isolated polynucleotidesmay encode an antibody or antigen-binding fragment thereof having alight chain CDR1 substantially the same as, or identical to, SEQ ID NO:1008, for example SEQ ID NO: 1007; a CDR2 encoded by a nucleotidesequence substantially the same as, or identical to, SEQ ID NO: 1010,for example SEQ ID NO: 1009; and a CDR3 encoded by a nucleotide sequencesubstantially the same as, or identical to, SEQ ID NO: 1012, for exampleSEQ ID NO: 1011; and a heavy chain CDR1 substantially the same as, oridentical to, SEQ ID NO: 864, for example SEQ ID NO: 863; a CDR2substantially the same as, or identical to, SEQ ID NO: 866, for exampleSEQ ID NO: 865; and a CDR3 substantially the same as, or identical to,SEQ ID NO: 868, for example SEQ ID NO: 867, defined according to IMGT.

In some embodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a light chain CDR1 sequencesubstantially the same as, or identical to, SEQ ID NO: 774, definedaccording to Kabat, for example SEQ ID NO: 773. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a light chain CDR2 substantially the same as, oridentical to, SEQ ID NO: 776, defined according to Kabat, for exampleSEQ ID NO: 775. In some embodiments, the isolated polynucleotides encodean antibody or antigen-binding fragment thereof having a light chainCDR3 substantially the same as, or identical to, SEQ ID NO: 778, definedaccording to Kabat, for example SEQ ID NO: 777. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a heavy chain CDR1 substantially the same as, oridentical to, SEQ ID NO: 642, defined according to Kabat, for exampleSEQ ID NO: 641. In some embodiments, the isolated polynucleotides encodean antibody or antigen-binding fragment thereof having a heavy chainCDR2 substantially the same as, or identical to, SEQ ID NO: 644, definedaccording to Kabat, for example SEQ ID NO: 643. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a heavy chain CDR3 substantially the same as, oridentical to, SEQ ID NO: 646, defined according to Kabat, for exampleSEQ ID NO: 645. The isolated polynucleotides may encode an antibody orantigen-binding fragment thereof having a light chain with a CDR1substantially the same as, or identical to, SEQ ID NO: 774, for exampleSEQ ID NO: 773; a CDR2 substantially the same as, or identical to, SEQID NO: 776, for example SEQ ID NO: 775; and a CDR3 substantially thesame as, or identical to, SEQ ID NO: 778, for example SEQ ID NO: 777,defined according to Kabat. The isolated polynucleotides may encode anantibody or antigen-binding fragment thereof having a heavy chain CDR1substantially the same as, or identical to, SEQ ID NO: 642, for exampleSEQ ID NO: 641; a CDR2 substantially the same as, or identical to, SEQID NO: 644, for example SEQ ID NO: 643; and a CDR3 substantially thesame as, or identical to, SEQ ID NO: 646, for example SEQ ID NO: 645,defined according to Kabat. The isolated polynucleotides may encode anantibody or antigen-binding fragment thereof having a light chain CDR1substantially the same as, or identical to, SEQ ID NO: 774, for exampleSEQ ID NO: 773; a CDR2 encoded by a nucleotide sequence substantiallythe same as, or identical to, SEQ ID NO: 776, for example SEQ ID NO:775; and a CDR3 encoded by a nucleotide sequence substantially the sameas, or identical to, SEQ ID NO: 778, for example SEQ ID NO: 777; and aheavy chain CDR1 substantially the same as, or identical to, SEQ ID NO:642, for example SEQ ID NO: 641; a CDR2 substantially the same as, oridentical to, SEQ ID NO: 644, for example SEQ ID NO: 643; and a CDR3substantially the same as, or identical to, SEQ ID NO: 646, for exampleSEQ ID NO: 645, defined according to Kabat.

In some embodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a light chain CDR1 sequencesubstantially the same as, or identical to, SEQ ID NO: 1044, definedaccording to IMGT, for example SEQ ID NO: 1043. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a light chain CDR2 substantially the same as, oridentical to, SEQ ID NO: 1046, defined according to IMGT, for exampleSEQ ID NO: 1045. In some embodiments, the isolated polynucleotidesencode an antibody or antigen-binding fragment thereof having a lightchain CDR3 substantially the same as, or identical to, SEQ ID NO: 1048,defined according to IMGT, for example SEQ ID NO: 1047. In someembodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a heavy chain CDR1 substantiallythe same as, or identical to, SEQ ID NO: 912, defined according to IMGT,for example SEQ ID NO: 911. In some embodiments, the isolatedpolynucleotides encode an antibody or antigen-binding fragment thereofhaving a heavy chain CDR2 substantially the same as, or identical to,SEQ ID NO: 914, defined according to IMGT, for example SEQ ID NO: 913.In some embodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a heavy chain CDR3 substantiallythe same as, or identical to, SEQ ID NO: 916, defined according to IMGT,for example SEQ ID NO: 915. The isolated polynucleotides may encode anantibody or antigen-binding fragment thereof having a light chain with aCDR1 substantially the same as, or identical to, SEQ ID NO: 1044, forexample SEQ ID NO: 1043; a CDR2 substantially the same as, or identicalto, SEQ ID NO: 1046, for example SEQ ID NO: 1045; and a CDR3substantially the same as, or identical to, SEQ ID NO: 1048, for exampleSEQ ID NO: 1047, defined according to IMGT. The isolated polynucleotidesmay encode an antibody or antigen-binding fragment thereof having aheavy chain CDR1 substantially the same as, or identical to, SEQ ID NO:912, for example SEQ ID NO: 911; a CDR2 substantially the same as, oridentical to, SEQ ID NO: 914, for example SEQ ID NO: 913; and a CDR3substantially the same as, or identical to, SEQ ID NO: 916, for exampleSEQ ID NO: 915, defined according to IMGT. The isolated polynucleotidesmay encode an antibody or antigen-binding fragment thereof having alight chain CDR1 substantially the same as, or identical to, SEQ ID NO:1044, for example SEQ ID NO: 1043; a CDR2 encoded by a nucleotidesequence substantially the same as, or identical to, SEQ ID NO: 1046,for example SEQ ID NO: 1045; and a CDR3 encoded by a nucleotide sequencesubstantially the same as, or identical to, SEQ ID NO: 1048, for exampleSEQ ID NO: 1047; and a heavy chain CDR1 substantially the same as, oridentical to, SEQ ID NO: 912, for example SEQ ID NO: 911; a CDR2substantially the same as, or identical to, SEQ ID NO: 914, for exampleSEQ ID NO: 913; and a CDR3 substantially the same as, or identical to,SEQ ID NO: 916, for example SEQ ID NO: 915, defined according to IMGT.

In some embodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a light chain CDR1 sequencesubstantially the same as, or identical to, SEQ ID NO: 846, definedaccording to Kabat, for example SEQ ID NO: 845. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a light chain CDR2 substantially the same as, oridentical to, SEQ ID NO: 848, defined according to Kabat, for exampleSEQ ID NO: 847. In some embodiments, the isolated polynucleotides encodean antibody or antigen-binding fragment thereof having a light chainCDR3 substantially the same as, or identical to, SEQ ID NO: 850, definedaccording to Kabat, for example SEQ ID NO: 849. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a heavy chain CDR1 substantially the same as, oridentical to, SEQ ID NO: 732, defined according to Kabat, for exampleSEQ ID NO: 731. In some embodiments, the isolated polynucleotides encodean antibody or antigen-binding fragment thereof having a heavy chainCDR2 substantially the same as, or identical to, SEQ ID NO: 734, definedaccording to Kabat, for example SEQ ID NO: 733. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a heavy chain CDR3 substantially the same as, oridentical to, SEQ ID NO: 736, defined according to Kabat, for exampleSEQ ID NO: 735. The isolated polynucleotides may encode an antibody orantigen-binding fragment thereof having a light chain with a CDR1substantially the same as, or identical to, SEQ ID NO:846, for exampleSEQ ID NO: 845; a CDR2 substantially the same as, or identical to, SEQID NO: 848, for example SEQ ID NO: 847; and a CDR3 substantially thesame as, or identical to, SEQ ID NO: 850, for example SEQ ID NO: 849,defined according to Kabat. The isolated polynucleotides may encode anantibody or antigen-binding fragment thereof having a heavy chain CDR1substantially the same as, or identical to, SEQ ID NO: 732, for exampleSEQ ID NO: 731; a CDR2 substantially the same as, or identical to, SEQID NO: 734, for example SEQ ID NO: 733; and a CDR3 substantially thesame as, or identical to, SEQ ID NO: 736, for example SEQ ID NO: 735,defined according to Kabat. The isolated polynucleotides may encode anantibody or antigen-binding fragment thereof having a light chain CDR1substantially the same as, or identical to, SEQ ID NO: 846, for exampleSEQ ID NO: 845; a CDR2 encoded by a nucleotide sequence substantiallythe same as, or identical to, SEQ ID NO: 848, for example SEQ ID NO:847; and a CDR3 encoded by a nucleotide sequence substantially the sameas, or identical to, SEQ ID NO: 850, for example SEQ ID NO: 849; and aheavy chain CDR1 substantially the same as, or identical to, SEQ ID NO:732, for example SEQ ID NO: 731; a CDR2 substantially the same as, oridentical to, SEQ ID NO: 734, for example SEQ ID NO: 733; and a CDR3substantially the same as, or identical to, SEQ ID NO: 736, for exampleSEQ ID NO: 735, defined according to Kabat.

In some embodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a light chain CDR1 sequencesubstantially the same as, or identical to, SEQ ID NO: 1116, definedaccording to IMGT, for example SEQ ID NO: 1115. In some embodiments, theisolated polynucleotides encode an antibody or antigen-binding fragmentthereof having a light chain CDR2 substantially the same as, oridentical to, SEQ ID NO: 1118, defined according to IMGT, for exampleSEQ ID NO: 1117. In some embodiments, the isolated polynucleotidesencode an antibody or antigen-binding fragment thereof having a lightchain CDR3 substantially the same as, or identical to, SEQ ID NO: 1120,defined according to IMGT, for example SEQ ID NO: 1119. In someembodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a heavy chain CDR1 substantiallythe same as, or identical to, SEQ ID NO: 1002, defined according toIMGT, for example SEQ ID NO: 1001. In some embodiments, the isolatedpolynucleotides encode an antibody or antigen-binding fragment thereofhaving a heavy chain CDR2 substantially the same as, or identical to,SEQ ID NO: 1004, defined according to IMGT, for example SEQ ID NO: 1003.In some embodiments, the isolated polynucleotides encode an antibody orantigen-binding fragment thereof having a heavy chain CDR3 substantiallythe same as, or identical to, SEQ ID NO: 1006, defined according toIMGT, for example SEQ ID NO: 1005. The isolated polynucleotides mayencode an antibody or antigen-binding fragment thereof having a lightchain with a CDR1 substantially the same as, or identical to, SEQ ID NO:1116, for example SEQ ID NO: 1115; a CDR2 substantially the same as, oridentical to, SEQ ID NO: 1118, for example SEQ ID NO: 1117; and a CDR3substantially the same as, or identical to, SEQ ID NO: 1120, for exampleSEQ ID NO: 1119, defined according to IMGT. The isolated polynucleotidesmay encode an antibody or antigen-binding fragment thereof having aheavy chain CDR1 substantially the same as, or identical to, SEQ ID NO:1002, for example SEQ ID NO: 1001; a CDR2 substantially the same as, oridentical to, SEQ ID NO: 1004, for example SEQ ID NO: 1003; and a CDR3substantially the same as, or identical to, SEQ ID NO: 1006, for exampleSEQ ID NO: 1005, defined according to IMGT. The isolated polynucleotidesmay encode an antibody or antigen-binding fragment thereof having alight chain CDR1 substantially the same as, or identical to, SEQ ID NO:1116, for example SEQ ID NO: 1115; a CDR2 encoded by a nucleotidesequence substantially the same as, or identical to, SEQ ID NO: 1118,for example SEQ ID NO: 1117; and a CDR3 encoded by a nucleotide sequencesubstantially the same as, or identical to, SEQ ID NO: 1120, for exampleSEQ ID NO: 1119; and a heavy chain CDR1 substantially the same as, oridentical to, SEQ ID NO: 1002, for example SEQ ID NO: 1001; a CDR2substantially the same as, or identical to, SEQ ID NO: 1004, for exampleSEQ ID NO: 1003; and a CDR3 substantially the same as, or identical to,SEQ ID NO: 1006, for example SEQ ID NO: 1005, defined according to IMGT.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 411, for example SEQ ID NO: 410. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 196, for example SEQ ID NO: 195. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 411, for example SEQ ID NO: 410; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 196, for exampleSEQ ID NO: 195. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 465, for example SEQ ID NO: 464. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 268, for example SEQ ID NO: 267. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 465, for example SEQ ID NO: 464; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 268, for exampleSEQ ID NO: 267. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 581, for example SEQ ID NO: 580. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 268, for example SEQ ID NO: 267. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 581, for example SEQ ID NO: 580; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 268, for exampleSEQ ID NO: 267. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 545, for example SEQ ID NO: 544. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 384, for example SEQ ID NO: 383. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 545, for example SEQ ID NO: 544; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 384, for exampleSEQ ID NO: 383. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 545, for example SEQ ID NO: 544. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 393, for example SEQ ID NO: 392. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 545, for example SEQ ID NO: 544; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 393, for exampleSEQ ID NO: 392. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 545, for example SEQ ID NO: 544. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 402, for example SEQ ID NO: 401. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 545, for example SEQ ID NO: 544; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 402, for exampleSEQ ID NO: 401. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 572, for example SEQ ID NO:571. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 384, for example SEQ ID NO: 383. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 572, for example SEQ ID NO: 571; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 384, for exampleSEQ ID NO: 383. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 572, for example SEQ ID NO: 571. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 393, for example SEQ ID NO: 392. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 572, for example SEQ ID NO: 571; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 393, for exampleSEQ ID NO: 392. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

Polynucleotides described herein may encode antibodies orantigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 572, for example SEQ ID NO: 571. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a heavy chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 402, for example SEQ ID NO: 401. In someembodiments the described isolated polynucleotides may encode antibodiesor antigen-binding fragments that have a light chain variable domainsegment that includes an amino acid sequence substantially the same as,or identical to, SEQ ID NO: 572, for example SEQ ID NO: 571; and a heavychain variable domain segment that includes an amino acid sequencesubstantially the same as, or identical to, SEQ ID NO: 402, for exampleSEQ ID NO: 401. The isolated polynucleotides capable of encoding thevariable domain segments provided herein may be included on the same, ordifferent, vectors to produce antibodies or antigen-binding fragments.

The polynucleotides capable of encoding the variable domain segmentsprovided herein may be included on the same, or different, vectors toproduce antibodies or antigen-binding fragments. Polynucleotidesencoding engineered antigen-binding proteins also are within the scopeof the disclosure. In some embodiments, the polynucleotides described(and the peptides they encode) include a leader sequence. Any leadersequence known in the art may be employed. The leader sequence mayinclude, but is not limited to, a restriction site or a translationstart site.

Also provided are vectors comprising the polynucleotides describedherein. The vectors can be expression vectors. Recombinant expressionvectors containing a sequence encoding a polypeptide of interest arethus contemplated as within the scope of this disclosure. The expressionvector may contain one or more additional sequences such as but notlimited to regulatory sequences (e.g., promoter, enhancer), a selectionmarker, and a polyadenylation signal. Vectors for transforming a widevariety of host cells are well known and include, but are not limitedto, plasmids, phagemids, cosmids, baculoviruses, bacmids, bacterialartificial chromosomes (BACs), yeast artificial chromosomes (YACs), aswell as other bacterial, yeast and viral vectors.

Recombinant expression vectors within the scope of the descriptioninclude synthetic, genomic, or cDNA-derived nucleic acid fragments thatencode at least one recombinant protein which may be operably linked tosuitable regulatory elements. Such regulatory elements may include atranscriptional promoter, sequences encoding suitable mRNA ribosomalbinding sites, and sequences that control the termination oftranscription and translation. Expression vectors, especially mammalianexpression vectors, may also include one or more nontranscribed elementssuch as an origin of replication, a suitable promoter and enhancerlinked to the gene to be expressed, other 5′ or 3′ flankingnontranscribed sequences, 5′ or 3′ nontranslated sequences (such asnecessary ribosome binding sites), a polyadenylation site, splice donorand acceptor sites, or transcriptional termination sequences. An originof replication that confers the ability to replicate in a host may alsobe incorporated.

The transcriptional and translational control sequences in expressionvectors to be used in transforming vertebrate cells may be provided byviral sources. Exemplary vectors may be constructed as described byOkayama and Berg, 3 Mol. Cell. Biol. 280 (1983).

In some embodiments, the antibody- or antigen-binding fragment-codingsequence is placed under control of a powerful constitutive promoter,such as the promoters for the following genes: hypoxanthinephosphoribosyl transferase (HPRT), adenosine deaminase, pyruvate kinase,beta-actin, human myosin, human hemoglobin, human muscle creatine, andothers. In addition, many viral promoters function constitutively ineukaryotic cells and are suitable for use with the describedembodiments. Such viral promoters include without limitation,Cytomegalovirus (CMV) immediate early promoter, the early and latepromoters of SV40, the Mouse Mammary Tumor Virus (MMTV) promoter, thelong terminal repeats (LTRs) of Maloney leukemia virus, HumanImmunodeficiency Virus (HIV), Epstein Barr Virus (EBV), Rous SarcomaVirus (RSV), and other retroviruses, and the thymidine kinase promoterof Herpes Simplex Virus. In one embodiment, the antibody orantigen-binding fragment thereof coding sequence is placed under controlof an inducible promoter such as the metallothionein promoter,tetracycline-inducible promoter, doxycycline-inducible promoter,promoters that contain one or more interferon-stimulated responseelements (ISRE) such as protein kinase R 2′,5′-oligoadenylatesynthetases, Mx genes, ADAR1, and the like.

Vectors described herein may contain one or more Internal Ribosome EntrySite(s) (IRES). Inclusion of an IRES sequence into fusion vectors may bebeneficial for enhancing expression of some proteins. In someembodiments the vector system will include one or more polyadenylationsites (e.g., SV40), which may be upstream or downstream of any of theaforementioned nucleic acid sequences. Vector components may becontiguously linked, or arranged in a manner that provides optimalspacing for expressing the gene products (i.e., by the introduction of“spacer” nucleotides between the ORFs), or positioned in another way.Regulatory elements, such as the IRES motif, may also be arranged toprovide optimal spacing for expression.

The vectors may comprise selection markers, which are well known in theart. Selection markers include positive and negative selection markers,for example, antibiotic resistance genes (e.g., neomycin resistancegene, a hygromycin resistance gene, a kanamycin resistance gene, atetracycline resistance gene, a penicillin resistance gene), glutamatesythase genes, HSV-TK, HSV-TK derivatives for ganciclovir selection, orbacterial purine nucleoside phosphorylase gene for 6-methylpurineselection (Gadi et al., 7 Gene Ther. 1738-1743 (2000)). A nucleic acidsequence encoding a selection marker or the cloning site may be upstreamor downstream of a nucleic acid sequence encoding a polypeptide ofinterest or cloning site.

The vectors described herein may be used to transform various cells withthe genes encoding the described antibodies or antigen-bindingfragments. For example, the vectors may be used to generate antibody orantigen-binding fragment-producing cells. Thus, another aspect featureshost cells transformed with vectors comprising a nucleic acid sequenceencoding an antibody or antigen-binding fragment thereof thatspecifically binds Tau, such as the antibodies or antigen-bindingfragments described and exemplified herein.

Numerous techniques are known in the art for the introduction of foreigngenes into cells and may be used to construct the recombinant cells forpurposes of carrying out the described methods, in accordance with thevarious embodiments described and exemplified herein. The technique usedshould provide for the stable transfer of the heterologous gene sequenceto the host cell, such that the heterologous gene sequence is heritableand expressible by the cell progeny, and so that the necessarydevelopment and physiological functions of the recipient cells are notdisrupted. Techniques which may be used include but are not limited tochromosome transfer (e.g., cell fusion, chromosome mediated genetransfer, micro cell mediated gene transfer), physical methods (e.g.,transfection, spheroplast fusion, microinjection, electroporation,liposome carrier), viral vector transfer (e.g., recombinant DNA viruses,recombinant RNA viruses) and the like (described in Cline, 29 Pharmac.Ther. 69-92 (1985)). Calcium phosphate precipitation and polyethyleneglycol (PEG)-induced fusion of bacterial protoplasts with mammaliancells may also be used to transform cells.

Cells suitable for use in the expression of the antibodies orantigen-binding fragments described herein are preferably eukaryoticcells, more preferably cells of plant, rodent, or human origin, forexample but not limited to NS0, CHO, CHOK1, perC.6, Tk-ts13, BHK, HEK293cells, COS-7, T98G, CV-1/EBNA, L cells, C127, 3T3, HeLa, NS1, and Sp2/0myeloma cells cell lines, among others. In addition, expression ofantibodies may be accomplished using hybridoma cells. Methods forproducing hybridomas are well established in the art.

Cells transformed with expression vectors described herein may beselected or screened for recombinant expression of the antibodies orantigen-binding fragments described herein. Recombinant-positive cellsare expanded and screened for subclones exhibiting a desired phenotype,such as high level expression, enhanced growth properties, or theability to yield proteins with desired biochemical characteristics, forexample, due to protein modification or altered post-translationalmodifications. These phenotypes may be due to inherent properties of agiven subclone or to mutation. Mutations may be effected through the useof chemicals, UV-wavelength light, radiation, viruses, insertionalmutagens, inhibition of DNA mismatch repair, or a combination of suchmethods.

In certain embodiments, an isolated cell line expressing any of theanti-Tau antibodies described herein are provided. In one embodiment,the isolated cell line is a hybridoma. In one embodiment, the isolatedcell line is the hybridoma from which monoclonal antibody 7G6 isproduced. In one embodiment, the isolated cell line is Freestyle® 293-Fcells from which 7G6-HCzu8-LCzu6-HEK is produced and which cell line hasbeen deposited with the American Type Culture Collection, Manassas, Va.,USA, on Oct. 11, 2017, with the ATCC Patent Deposit DesignationPTA-124523. In one embodiment, the isolated cell line is Freestyle®293-F cells from which 7G6-HCzu25-LCzu18-HEK is produced and which cellline has been deposited with the American Type Culture Collection,Manassas, Va., USA, on Oct. 11, 2017, with the ATCC Patent DepositDesignation PTA-124524.

Cells that express the provided anti-Tau antibodies or antigen-bindingfragments provided herein may be employed in methods of producing theanti-Tau antibodies or antigen-binding fragments by culturing the cellsunder conditions suitable for expression of the respective antibody orantigen-binding fragment. In some embodiments, the anti-Tau antibody orantigen-binding fragment is recovered from the culture medium.

In certain embodiments, any of the antibodies or antigen-bindingfragments that specifically bind Tau as provided herein is useful fordetecting the presence of Tau in a biological sample. The term“detecting” as used herein encompasses quantitative or qualitativedetection. In certain embodiments, the biological sample may be derivedfrom a cell or tissue, such as cerebrospinal fluid, a cell or tissue ofthe brain (e.g., cortex or hippocampus), or blood, a histologicalpreparation, and the like. In some embodiments the described methodsinclude detecting Tau in a sample by contacting the biological samplewith:

-   -   (a) any one of antibody ms7G6, antibody 7G6-HCzu8-LCzu6,        antibody 7G6-HCzu8-LCzu21, antibody 7G6-HCzu23-LCzu15, antibody        7G6-HCzu24-LCzu15, antibody 7G6-HCzu25-LCzu15, antibody        7G6-HCzu23-LCzu18, antibody 7G6-HCzu24-LCzu18, antibody        7G6-HCzu25-LCzu18, or an antigen-binding fragment thereof;    -   (b) an antibody, or antigen-binding fragment thereof, that        comprises heavy chain CDR1, CDR2, and CDR3 amino acid sequences        and light chain CDR1, CDR2, and CDR3 amino acid sequences of        antibody ms7G6, antibody 7G6-HCzu8-LCzu6, or antibody        7G6-HCzu25-LCzu18, as described in Table 1;    -   (c) an antibody, or antigen-binding fragment thereof, that        comprises the heavy chain variable domain segment and light        chain variable domain segment of any one of antibody ms7G6,        antibody 7G6-HCzu8/LCzu6, antibody 7G6-HCzu8/LCzu21, antibody        7G6-HCzu23/LCzu15, antibody 7G6-HCzu24/LCzu15, antibody        7G6-HCzu25/LCzu15, antibody 7G6-HCzu23/LCzu18, antibody        7G6-HCzu24/LCzu18, or antibody 7G6-HCzu25/LCzu18, as described        in Table 1; or    -   (d) an antibody having the amino acid sequence of antibody        produced by any one of the cell lines deposited with the ATCC        having accession number PTA-124523 or PTA-124524, or an antigen        binding fragment thereof.

In certain embodiments, the method comprises contacting the biologicalsample with an anti-Tau antibody as provided herein under conditionspermissive for binding of the anti-Tau antibody to Tau, and detectingwhether a complex is formed between the anti-Tau antibody and Tau. Insome embodiments of these methods, the anti-Tau antibody is detectablylabelled. The method may be an in vitro or in vivo method. The complexformed between the anti-Tau antibody and Tau in a test biological samplecan be compared to the complex formed in a control biological sample(e.g., a biological sample from a healthy subject). The amount of thecomplex formed between the anti-Tau antibody and Tau in a testbiological sample can also be quantified and compared to the amount ofthe complex formed in a control biological sample or to the averageamount of the complex known to be formed in healthy subjects.

In a further aspect, the invention provides pharmaceutical formulationscomprising any of the antibodies or antigen-binding fragments thatspecifically bind Tau as described herein, e.g., for use in any of thetherapeutic methods provided herein. In some embodiments, apharmaceutical formulation comprises any of the antibodies orantigen-binding fragments that specifically bind Tau provided herein anda pharmaceutically acceptable carrier.

Pharmaceutical formulations of an anti-Tau antibody or antigen-bindingfragment as described herein are prepared by mixing such antibody orantigen-binding fragment having the desired degree of purity with one ormore optional pharmaceutically acceptable carriers, diluents, and/orexcipients (Remington's Pharmaceutical Sciences 16th edition, Osol, A.Ed. (1980)), in the form of lyophilized formulations or aqueoussolutions. Pharmaceutically acceptable carriers, diluents, andexcipients are generally nontoxic to recipients at the dosages andconcentrations employed, and include, but are not limited to: sterilewater, buffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid and methionine; preservatives (suchas octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride; benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides, and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionicsurfactants such as polyethylene glycol (PEG). Exemplarypharmaceutically acceptable carriers herein further include interstitialdrug dispersion agents such as soluble neutral-active hyaluronidaseglycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidaseglycoproteins, such as rHuPH20 (HYLENEX™, Baxter International, Inc.).Certain exemplary sHASEGPs and methods of use, including rHuPH20, aredescribed in U.S. Pat. No. 7,871,607 and U.S. Publication No.2006/0104968. In one aspect, a sHASEGP is combined with one or moreadditional glycosaminoglycanases such as chondroitinases.

Exemplary lyophilized antibody formulations are described in U.S. Pat.No. 6,267,958. Aqueous antibody formulations include those described inU.S. Pat. No. 6,171,586 and WO2006/044908, the latter formulationsincluding a histidine-acetate buffer.

The anti-Tau antibody or antigen-binding fragment as an activeingredient in a pharmaceutical formulation may be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the antibody, which matrices are in theform of shaped articles, e.g. films, or microcapsules.

The formulations to be used for in vivo administration are generallysterile. Sterility may be readily accomplished, e.g., by filtrationthrough sterile filtration membranes.

Any of the antibodies or antigen-binding fragments that specificallybind Tau (or formulations thereof) provided herein may be used intherapeutic methods.

In one aspect, an anti-Tau antibody or antigen-binding fragment for useas a medicament is provided. In some embodiments, an anti-Tau antibodyor antigen-binding fragment for use in the reduction of insoluble Tau isprovided. In some embodiments, an anti-Tau antibody or antigen-bindingfragment for use in inhibiting Tau aggregation is provided. In furtheraspects, an anti-Tau antibody or antigen-binding fragment for use intreating a Tauopathy is provided. Exemplary Tauopathies that can betreated with the disclosed anti-Tau antibodies or antigen-bindingfragments include Alzheimer's disease (AD), progressive supranuclearpalsy (PSP), and frontotemporal dementia (FTD). An exemplary FTD thatcan be treated is Pick's disease (PiD).

In certain embodiments, an anti-Tau antibody or antigen-binding fragmentfor use in a method of treatment is provided. In some embodiments, ananti-Tau antibody or antigen-binding fragment for use in a method ofreducing insoluble Tau in a subject is provided. In some embodiments, ananti-Tau antibody or antigen-binding fragment for use in a method ofinhibiting Tau aggregation in a subject is provided. In certainembodiments, an anti-Tau antibody or antigen-binding fragment for use ina method of treating a subject having a Tauopathy is provided. Themethod of treatment of a Tauopathy comprises administering to thesubject the anti-Tau antibody or antigen-binding fragment in an amounteffective to treat the Tauopathy. In certain embodiments, the Tauopathyis any one of the Tauopathies described above. In preferred embodiments,the subject is a mammal, preferably a human.

In a further aspect, also provided herein is the use of an anti-Tauantibody or antigen-binding fragment as described herein in themanufacture or preparation of a medicament. In some embodiments, themedicament is for reduction of insoluble Tau. In some embodiments, themedicament is for inhibition of Tau aggregation. In some embodiments,the medicament is for treatment of a Tauopathy. In certain embodiments,the Tauopathy is any one of the Tauopathies described above.

An anti-Tau antibody or antigen-binding fragment as described herein canbe administered by any suitable means, including parenteral,intrapulmonary, and intranasal, and, if desired for local treatment,intralesional administration. Parenteral infusions includeintramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration. Dosing can be by any suitable route, e.g.by injections, such as intravenous or subcutaneous injections, dependingin part on whether the administration is brief or chronic. Variousdosing schedules including but not limited to single or multipleadministrations over various time-points, bolus administration, andpulse infusion are contemplated herein.

The anti-Tau antibodies or antigen-binding fragments provided herein areto be formulated, dosed, and administered in a fashion consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners.

For the prevention or treatment of disease, the appropriate dosage ofthe anti-Tau antibody or antigen-binding fragment will depend on thetype of disease to be treated, the type of antibody, the severity andcourse of the disease, whether the antibody or antigen-binding fragmentis administered for preventive or therapeutic purposes, previoustherapy, the patient's clinical history and response to the antibody,and the discretion of the attending physician. The antibody orantigen-binding fragment is suitably administered to the patient at onetime or over a series of treatments. Depending on the type and severityof the disease, about 1 μg/kg to 15 mg/kg of antibody or antigen-bindingfragment can be an initial candidate dosage for administration to thepatient, whether, for example, by one or more separate administrations,or by continuous infusion. One typical daily dosage might range fromabout 1 μg/kg to 100 mg/kg or more, depending on the factors mentionedabove. For repeated administrations over several days or longer,depending on the condition, the treatment would generally be sustaineduntil a desired suppression of disease symptoms occurs. One exemplarydosage of the antibody or antigen-binding fragment would be in the rangefrom about 0.05 mg/kg to about 100 mg/kg. Thus, one or more doses ofabout 0.5 mg/kg, 2.0 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg (or anycombination thereof) may be administered to the patient. Such doses maybe administered intermittently, for example, every week or every threeweeks (e.g. such that the patient receives from about two to abouttwenty, or e.g. about six doses of the antibody). An initial higherloading dose, followed by one or more lower doses may be administered.However, other dosage regimens may be useful. The progress of thistherapy may be monitored by conventional techniques and assays.

Also provided herein is an article of manufacture containing material(s)useful for the treatment, prevention and/or diagnosis of the disordersdescribed above. The article of manufacture comprises a container and alabel or package insert on or associated with the container. Suitablecontainers include, for example, bottles, vials, syringes, IV solutionbags, etc. The containers may be formed from a variety of materials suchas glass or plastic. The container holds a composition which is byitself or combined with another composition effective for treating,preventing and/or diagnosing the condition and may have a sterile accessport (for example the container may be an intravenous solution bag or avial having a stopper pierceable by a hypodermic injection needle). Theactive agent in the composition is an anti-Tau antibody orantigen-binding fragment as described herein. The label or packageinsert indicates that the composition is used for treating the conditionof choice. Alternatively, or additionally, the article of manufacturemay further comprise a second container comprising apharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

ILLUSTRATIVE EMBODIMENTS

Provided here are illustrative embodiments of the disclosed technology.These embodiments are illustrative only and do not limit the scope ofthe present disclosure or of the claims attached hereto.

Embodiment 1. A monoclonal antibody, or an antigen-binding fragmentthereof, that specifically binds a human Tau, the antibody comprising:

-   -   a heavy chain complementarity determining region 1 (HCDR1), a        heavy chain complementarity determining region 2 (HCDR2), and a        heavy chain complementarity determining region 3 (HCDR3) as set        forth in SEQ ID NO: 196 and a light chain complementarity        determining region 1 (LCDR1), a light chain complementarity        determining region 2 (LCDR2), and a light chain complementarity        determining region 3 (LCDR3) as set forth in SEQ ID NO: 411;    -   a HCDR1, a HCDR2, and a HCDR3 as set forth in SEQ ID NO: 268 and        a LCDR1, a LCDR2, and a LCDR3 as set forth in SEQ ID NO: 465; or    -   a HCDR1, a HCDR2, and a HCDR3 as set forth in SEQ ID NO: 402 and        a LCDR1, a LCDR2, and a LCDR3 as set forth in SEQ ID NO: 572.

Embodiment 2. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 1, wherein:

-   -   the HCDR1 comprises SEQ ID NO: 594, the HCDR2 comprises SEQ ID        NO: 596, the HCDR3 comprises SEQ ID NO: 598, the LCDR1 comprises        SEQ ID NO: 738, the LCDR2 comprises SEQ ID NO: 740, and the        LCDR3 comprises SEQ ID NO: 742 as defined according to the        method of Kabat;    -   the HCDR1 comprises SEQ ID NO: 864, the HCDR2 comprises SEQ ID        NO: 866, the HCDR3 comprises SEQ ID NO: 868, the LCDR1 comprises        SEQ ID NO: 1008, the LCDR2 comprises SEQ ID NO: 1010, and the        LCDR3 comprises SEQ ID NO: 1012 as defined by IMGT;    -   the HCDR1 comprises SEQ ID NO: 642, the HCDR2 comprises SEQ ID        NO: 644, the HCDR3 comprises SEQ ID NO: 646, the LCDR1 comprises        SEQ ID NO: 774, the LCDR2 comprises SEQ ID NO: 776, and the        LCDR3 comprises SEQ ID NO: 778 as defined according to the        method of Kabat;    -   the HCDR1 comprises SEQ ID NO: 912, the HCDR2 comprises SEQ ID        NO: 914, the HCDR3 comprises SEQ ID NO: 916, the LCDR1 comprises        SEQ ID NO: 1044, the LCDR2 comprises SEQ ID NO: 1046, and the        LCDR3 comprises SEQ ID NO: 1048 as defined by IMGT;    -   the HCDR1 comprises SEQ ID NO: 732, the HCDR2 comprises SEQ ID        NO: 734, the HCDR3 comprises SEQ ID NO: 736, the LCDR1 comprises        SEQ ID NO: 846, the LCDR2 comprises SEQ ID NO: 848, and the        LCDR3 comprises SEQ ID NO: 850 as defined according to the        method of Kabat; or    -   the HCDR1 comprises SEQ ID NO: 1002, the HCDR2 comprises SEQ ID        NO: 1004, the HCDR3 comprises SEQ ID NO: 1006, the LCDR1        comprises SEQ ID NO: 1116, the LCDR2 comprises SEQ ID NO: 1118,        and the LCDR3 comprises SEQ ID NO: 1120 as defined by IMGT.

Embodiment 3. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 1 or 2, wherein the residue at position 49 ofthe light chain according to the method of Kabat is not cysteine.

Embodiment 4. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 3, wherein the residue at position 49 of thelight chain according to the method of Kabat is serine.

Embodiment 5. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the residue at position 57of the heavy chain according to the method of Kabat is not cysteine.

Embodiment 6. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 5, wherein the residue at position 57 of theheavy chain according to the method of Kabat is serine.

Embodiment 7. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the residue at position 34of the light chain according to the method of Kabat is glutamate.

Embodiment 8. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the residue at position 36of the light chain according to the method of Kabat is notphenylalanine.

Embodiment 9. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 8 wherein the residue at position 36 of thelight chain according to the method of Kabat is tyrosine.

Embodiment 10. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the residue at position 46of the light chain according to the method of Kabat is not arginine.

Embodiment 11. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 10 wherein the residue at position 46 of thelight chain according to the method of Kabat is leucine.

Embodiment 12. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the residue at position 94of the heavy chain according to the method of Kabat is not lysine.

Embodiment 13. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the residue at position 71of the heavy chain according to the method of Kabat is not arginine.

Embodiment 14. The monoclonal antibody or antigen-binding fragmentaccording to the method of Embodiment 13 wherein position 71 of theheavy chain according to the Kabat method is valine.

Embodiment 15. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 1 or Embodiment 2, the antibody comprising:

-   -   a heavy chain variable domain (HCVD) comprising SEQ ID NO: 268        and a light chain variable domain (LCVD) comprising SEQ ID NO:        465;    -   a HCVD comprising SEQ ID NO: 268 and a LCVD comprising SEQ ID        NO: 581;    -   a HCVD comprising SEQ ID NO: 384 and a LCVD comprising SEQ ID        NO: 545;    -   a HCVD comprising SEQ ID NO: 393 and a LCVD comprising SEQ ID        NO: 545;    -   a HCVD comprising SEQ ID NO: 402 and a LCVD comprising SEQ ID        NO: 545;    -   a HCVD comprising SEQ ID NO: 384 and a LCVD comprising SEQ ID        NO: 572;    -   a HCVD comprising SEQ ID NO: 393 and a LCVD comprising SEQ ID        NO: 572; or a HCVD comprising SEQ ID NO: 402 and a LCVD        comprising SEQ ID NO: 572.

Embodiment 16. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment, wherein the antibody is producedby the cell line having ATCC deposit number PTA-124523.

Embodiment 17. The monoclonal antibody or antigen-binding fragmentaccording to any one of Embodiments 1 to 15, wherein the antibody isproduced by the cell line having ATCC deposit number PTA-124524.

Embodiment 18. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment, wherein the antibody is a murineantibody, a chimeric antibody, or a humanized antibody.

Embodiment 19. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the antibody is IgG1.

Embodiment 20. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the antibody bindsmonomeric wild-type human 2N4R Tau with a K_(D) of less than about 0.5nM as measured by surface plasmon resonance.

Embodiment 21. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment, wherein the antibody orantigen-binding fragment binds to human Tau at an epitope comprising theamino acid sequence HVPG (SEQ ID NO: 1133).

Embodiment 22. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 21, wherein the antibody or antigen-bindingfragment is biepitopic and binds to human Tau at an epitope comprisingthe amino acid sequence HVPG (SEQ ID NO: 1133) within repeat region 2 orrepeat region 4.

Embodiment 23. The monoclonal antibody or antigen-binding fragmentaccording to any one of Embodiments 1 to 20, wherein the antibody orantigen-binding fragment binds to human Tau at an epitope comprising theamino acid sequence HVPGG (SEQ ID NO: 79).

Embodiment 24. The monoclonal antibody or antigen-binding fragmentaccording to Embodiment 23, wherein the antibody or antigen-bindingfragment is biepitopic and binds to human Tau at an epitope comprisingthe amino acid sequence HVPGG (SEQ ID NO: 79) within repeat region 2 orrepeat region 4.

Embodiment 25. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment,

-   -   wherein the antibody or antigen-binding fragment binds human Tau        at the epitope comprising the amino acid sequence HVPGG (SEQ ID        NO: 79) within repeat region 2 with a binding preference that is        at least about 10-fold greater than binding at an epitope        comprising the amino acid sequence HKPGG (SEQ ID NO: 182) within        repeat region 3 or than binding at an epitope comprising the        amino acid sequence HQPGG (SEQ ID NO: 183) within repeat region        1, or    -   wherein the antibody or antigen-binding fragment binds human Tau        at the epitope comprising the amino acid sequence HVPGG (SEQ ID        NO: 79) within repeat region 4 with a binding preference that is        at least about 10-fold greater than binding at an epitope        comprising the amino acid sequence HKPGG (SEQ ID NO: 182) within        repeat region 3 or than binding at an epitope comprising the        amino acid sequence HQPGG (SEQ ID NO: 183) within repeat region        1,        as determined by a peptide binding assay.

Embodiment 26. The monoclonal antibody or antigen-binding fragmentaccording to any preceding Embodiment wherein the antibody orantigen-binding fragment does not bind Tau at an epitope comprising theamino acid sequence HVSGG (SEQ ID NO: 184) within repeat region 2 or atan epitope comprising the amino acid sequence HVLGG (SEQ ID NO: 185)within repeat region 2.

Embodiment 27. A labeled antibody or antigen-binding fragment comprisingthe antibody or antigen-binding fragment according to any precedingEmbodiment.

Embodiment 28. A nucleic acid molecule encoding the monoclonal antibodyor antigen-binding fragment of any one of Embodiments 1 to 26.

Embodiment 29. A vector comprising the nucleic acid molecule ofEmbodiment 28.

Embodiment 30. A cell that expresses the nucleic acid molecule ofEmbodiment 28.

Embodiment 31. A method of producing an anti-Tau antibody orantigen-binding fragment comprising culturing a cell according toEmbodiment 30 under conditions suitable for producing the antibody orantigen-binding fragment.

Embodiment 32. The method according to Embodiment 31 further comprisingrecovering the antibody or antigen-binding fragment.

Embodiment 33. A pharmaceutical composition comprising the antibody orantigen-binding fragment of any one of Embodiments 1 to 26 and apharmaceutically acceptable carrier.

Embodiment 34. The antibody or antigen-binding fragment according to anyone of Embodiments 1 to 26 for use as a medicament.

Embodiment 35. The antibody or antigen-binding fragment according to anyone of Embodiments 1 to 26 for use in the treatment of a Tauopathy.

Embodiment 36. The antibody or antigen-binding fragment according to anyone of Embodiments 1 to 26 for use in the preparation of a medicamentfor the treatment of a Tauopathy.

Embodiment 37. The antibody for use in accordance with Embodiment 35 or36 wherein the Tauopathy is Alzheimer's disease, frontotemporaldementia, or progressive supranuclear palsy.

Embodiment 38. The antibody for use in accordance with Embodiment 37wherein the frontotemporal dementia is Pick's Disease.

Embodiment 39. A method for decreasing sarkosyl-insoluble Tau levels,the method comprising administering to the subject the monoclonalantibody or antigen-binding fragment of any one of Embodiments 1 to 26.

Embodiment 40. A method for inhibiting Tau aggregation, the methodcomprising administering to the subject the monoclonal antibody orantigen-binding fragment of any one of Embodiments 1 to 26.

Embodiment 41. The method according to Embodiment 39 or 40 wherein themethod is performed in vitro or in vivo.

Embodiment 42. A method of treating a Tauopathy in a subject, the methodcomprising: administering to the subject the monoclonal antibody orantigen-binding fragment of any one of Embodiments 1 to 26 underconditions effective to treat the Tauopathy in the subject.

Embodiment 43. The method according to Embodiment 42, wherein theTauopathy is Alzheimer's disease, frontotemporal dementia, orprogressive supranuclear palsy.

Embodiment 44. The method according to Embodiment 43, wherein thefrontotemporal dementia is Pick's disease.

The following examples are provided to supplement the prior disclosureand to provide a better understanding of the subject matter describedherein. These examples should not be considered to limit the describedsubject matter. It is understood that the examples and embodimentsdescribed herein are for illustrative purposes only and that variousmodifications or changes in light thereof will be apparent to personsskilled in the art and are to be included within the scope of theinvention and can be made without departing from the true scope of theinvention.

Example 1: Generation of Monoclonal Antibodies

To generate anti-Tau antibodies recognizing the microtubule bindingregion (MTBR) of Tau, the peptide sequence CNIKHVPGGGSVQIVYKPVD (SEQ IDNO: 186) (Peptide antigen) was synthesized. Residues 2-20 of SEQ ID NO:186 correspond to the amino acid sequence that spans the juncturebetween the second (i.e. not present in the 3R isoform) and third repeatregions of Tau (FIG. 2 ). The sequence also includes the hexapeptidemotif known as PHF6 (VQIVYK) (SEQ ID NO: 187) (von Bergen et al., PNAS,2000, 97(10): 5129-5134), which is one of the sites that initiates theaggregation of Tau. Peptide antigen was coupled to the Keyhole LimpetHemocyannin (KLH) carrier protein via the N-terminal cysteine residuethat does not naturally occur in the full length Tau-441 human proteinsequence. The final immunogen was prepared by mixing the Peptideantigen-conjugated KLH with Freund's complete adjuvant (1:2 (v/v)). Tauknockout mice (Jackson #007251) were immunized with mL per mouse of a2.5 mg/mL immunogen solution. Approximately 3 weeks following theinitial injection, the mice received a boost immunization with Peptideantigen-conjugated KLH without adjuvant at 0.05 mL per mouse at the sameprotein concentration as before.

One month after the boost immunization, antisera were collected from themice and antibody titers assessed by ELISA to measure immunoreactivityagainst the original immunizing Tau peptide and both 2N4R and 1N3Rrecombinant Tau proteins. Briefly, either 150 ng of Peptide antigenconjugated to BSA or 50 ng of 2N4R or 1N3R recombinant Tau protein (EnzoLife Sciences, cat. no's BML-SE321 and BML-SE323 respectively) were usedto coat each well of a 96-well plate (Costar cat. no. 2797) in 10 mMphosphate buffer, pH 7.0 at 37° C. for 1 hour. Plates were blocked in afinal concentration of 1% BSA diluted in PBS at room temperature for 30minutes. Blocking solution was removed and various dilutions ofanti-sera in the same blocking buffer were added to the plate for 1 hourat room temperature. The plate was washed several times with PBS priorto the addition of an HRP-labelled anti-mouse IgG antibody for 30minutes at room temperature. Following additional wash steps, antibodybinding was detected by addition of 3,3′,5,5′-Tetramethylbenzidine (TMB)substrate. The enzymatic reaction was stopped with an equal volume of 2MH₂SO₄ and the well optical density was determined using a platereader atwavelength 450 nm.

Once mice with a high antibody titer had been determined, cells wereisolated from the medial iliac lymph nodes and fused using polyethyleneglycol with mouse myeloma SP2 cells to generate hybridomas. Fused cellswere seeded into 96-well plates and cultured inhypoxanthine-aminopterin-thymidine (HAT) selection medium. Culturesupernatants were initially screened for Tau binding using the standardpeptide and recombinant Tau ELISA assays as detailed in the previousparagraph. To give an approximation of relative binding, culturesupernatant that was positive in the peptide ELISA and eitherrecombinant protein, 2N4R or 1N3R, or both, were then evaluated in acompetitive ELISA system. A 96-well plate was coated with 2N4Rrecombinant Tau, blocked and washed as before. At the primary antibodystep, culture supernatant was diluted 1 in 10 and incubated withdifferent dilutions of free antigen (2N4R Tau) for 1 hour at roomtemperature before addition to the plate. Once antibody/antigencomplexes were added to the plate, the protocol for the remainder of theassay was identical to the standard ELISA procedure. Single cell cloneswere confirmed by serial dilution and microscopy. The resulting finalhybridomas were cryopreserved in serum free medium.

Antibody Purification from Hybridomas

Hybridomas were grown in Hybridoma-SFM (Life Technologies) mediacontaining 1% FBS, 1 ng/mL human IL-6 (R&D Systems) andPenicillin/Streptomycin. Cultures were scaled up to 100 mL andsupernatant was harvested when cells reached a high density and wereapproximately 30% viable. Antibody was purified using Protein G columns,eluted with glycine/HCl, pH2.5 and immediately neutralized. Purifiedantibody was then dialyzed into 25 mM sodium phosphate (pH6.5) and 150mM NaCl, aliquoted, and stored at −80° C.

Hybridoma clones generating antibodies that recognized the originalimmunization peptide and full length recombinant 2N4R Tau protein wereproduced (Table 2).

Example 2: Affinity of Murine Antibodies to Recombinant Monomeric TauProtein Expressed in E. coli

Kinetic analysis of the interaction of the anti-Tau mouse monoclonalantibodies generated in Example 1 with human wild type Tau (2N4R) andthe equivalent P301S mutant Tau protein was conducted using a BIAcore™T100 instrument. Recombinant human full length Tau proteins wereexpressed in E. coli and then purified by Cellufine™ phosphate affinitychromatography followed by ammonium sulfate precipitation and reversephase HPLC chromatography.

Purified antibodies from hybridomas were captured by protein A/Gimmobilized on a CMS sensor chip (GE Healthcare). The wild type andP301S Tau proteins were then injected onto the sensor chip at fivedifferent concentrations and the affinity (equilibrium dissociationconstant, K_(D)) was calculated according to the manufacturer'sinstruction. The results are shown in Table 2.

TABLE 2 Calculated affinity of seven anti-Tau mouse antibodies to 2N4Rwild-type and P301S mutant recombinant Tau proteins. Wild type 2N4RP301S-2N4R Fold Antibody Isotype Tau K_(D) (nM) Tau K_(D) (nM)difference 6B2 IgG1, k 1.3 108 83.1 8E5 IgG2b, k 0.39 3.35 8.6 4E6 IgG1,k 1.0 33.5 33.5 5D1 IgG1, k 0.9 10.1 11.2 1F1 IgG2a, k 0.41 1.42 3.5 5H7IgG2a, k 0.61 3.8 6.2 7G6 IgG2b, k 0.052 0.57 11.0

Example 3: Fine Epitope Mapping of the ms7G6 Antibody

The recognition sequence of the murine 7G6 (“ms7G6” or “7G6”) antibodyagainst the full length wild type 2N4R human Tau protein sequence(Tau441) was fine epitope-mapped using peptide chip microarrays.

All procedures were performed by PEPperPrint GmbH, Germany. The fulllength 2N4R wild type human Tau sequence was elongated with a neutralGSGSGSG linker sequence (SEQ ID NO: 188) at the C-terminus andtranslated into overlapping 15-mer peptides. The resulting peptidemicroarray containing 441 different peptides was printed in duplicateonto a glass chip along with 82 spots of an additional HA-tag controlpeptide (YPYDVPDYAG) (SEQ ID NO: 189).

The ms7G6 anti-Tau antibody was diluted to a concentration of 111 g/mLin PBS (pH 7.4) containing 0.05% Tween 20 and 10% Rockland blockingbuffer (MB-070). The diluted antibody was incubated on the chip for 16hours at 4° C. with shaking at 140 rpm. Primary antibody was removed andthe chip was washed in PBS (pH 7.4)/0.05% Tween 20. Wash buffer wasremoved and goat anti-mouse IgG (H+L) DyLight™680 (1:5000) and ananti-HA tag DyLight™ 800 (1:2000) in the same buffer as the primaryantibody was then incubated for 45 minutes at room temperature on thechip. Detection antibody was removed and the chip was washed once againas previously. Fluorescence images were acquired on the LI-COR Odyssey™Imaging System and the microarray data was finally analyzed using thePepSlide™ Analyser software.

The fluorescent image of the chip (FIG. 3A) and resulting intensity plot(FIG. 3B) show that ms7G6 binds to two major sites on the full lengthTau protein. It was also found that the minimum required sequence forms7G6 binding at both sites is HVPGG (SEQ ID NO: 79) which is found atamino acid positions 299 to 303 (in the second repeat) and 362 to 366(in the fourth repeat). Minor binding was observed at two additionalsites: HQPGG (SEQ ID NO: 183) at amino acid positions 268 to 272, andHKPGG (SEQ ID NO: 182) at positions 330 to 334. Calculation of averagesignal intensities demonstrated that the mouse 7G6 antibody showed a41-fold or 38-fold preference in binding to the HVPGG (SEQ ID NO: 79)site normally contained within the second repeat region of full length4R Tau compared to the HQPGG (SEQ ID NO: 183) (repeat region 1) or HKPGG(SEQ ID NO: 182) (repeat region 3) sequences, respectively. Similarly, a35-fold or 33-fold preference in binding to the HVPGG (SEQ ID NO: 79)site normally contained within the fourth repeat region of full length4R Tau compared to the HQPGG (SEQ ID NO: 183) (repeat region 1) or HKPGG(SEQ ID NO: 182) (repeat region 3) sequences, respectively, wasobserved.

Example 4: 7G6 Epitope Substitution Scanning

To determine the amino acid stringency of the epitope recognized by thems7G6 antibody, substitution scanning of the naturally occurring Taupeptide sequence ‘KDNIKHVPGGGSVQI’ 5 (SEQ ID NO: 26) was performed. Allprocedures were undertaken by PEPperPrint GmbH, Germany and were basedupon an exchange of all positions in the starting peptide with each ofthe 20 naturally-occurring amino acids.

Every possible 15-mer peptide was synthesized and printed in triplicateonto a glass chip to give a microarray containing 900 peptide spots.Additional copies of the wild type peptide as well as the HA-tag controlpeptide were also spotted onto the chip as controls. The peptide chipwas then probed with ms7G6 under the same conditions as described inExample 3 (Fine epitope mapping of the ms7G6 antibody) and the resultingdata analyzed using the PepSlide™ Analyser software (FIG. 4 illustratingresults with SEQ ID NOs: 38 to 78). The substitution scanning showedthat, within the peptide epitope of ¹HVPGG⁵ (SEQ ID NO: 79), antibodyms7G6 shows some flexibility in the second position with a number ofpossible residues. There is also some binding when the 5^(th) amino acid(glycine) is substituted to either an alanine or serine. The middleproline residue is needed for antibody binding and may not besubstituted with any other naturally-occurring amino acid. This aminoacid can correspond to the P301 residue (within amino acids 299 to 303of Tau441, Uniprot accession number P10636-8) which is commonly mutatedto a serine or leucine residue to mimic human Tauopathy in a number ofpreclinical in vitro and in vivo models. The substitution scanning dataindicates that the ms7G6 antibody preferentially recognizes the aminoacid sequence HVPGG (SEQ ID NO: 79) binding site at amino acids 362-366in the mutant P301S protein.

Example 5: In Vitro Tau Aggregation

To determine whether the ms7G6 antibody could functionally inhibit Tauaggregation in vitro, aggregation assays were performed with recombinantTau protein.

Wild type or P301S mutant Tau protein was diluted to a concentration of60 μM in buffer containing 25 mM HEPES (pH 7.4), 100 mM NaCl and 0.5 mMTCEP in a final volume of 20 μl. The mixture was heated in a thermalcycler at 98° C. for 30 minutes and then allowed to cool to roomtemperature. Mouse IgG2b control or ms7G6 antibodies were diluted to afinal concentration of 8.3 μM in 25 mM HEPES (pH7.4), 100 mM NaCl andHALT Protease and Phosphatase inhibitors. Diluted antibodies or buffercontrols were mixed with the Tau proteins and incubated at 37° C. for 30minutes. To induce Tau aggregation, heparin was added to each reactionto a 12 μM final concentration in a final volume of 100 pI. The finalreaction conditions were 12 μM Tau, 8.3 μM antibody, 0.1 mM TCEP and 12μM Heparin in 25 mM HEPES pH7.4/100 mM NaCl buffer. The final reactionmixtures were incubated at 37° C. for at least 6 days with samplingthroughout to measure Tau aggregation.

The aggregation of Tau was measured on days 0, 1, 2, 5 and 6 by removing10 of the reaction mixture and placing into a 384-well, black-bottomedplate (Greiner). Thioflavin S dye was added to each well to a finalconcentration of 15 and the plate was incubated at room temperature inthe dark for 30 minutes. Fluorescence was measured on a Pherastar™platereader with excitation and emission wavelengths at 485 nm and 520nm, respectively.

As shown in FIGS. 5A and 5B, the degree and rate of heparin-inducedaggregation was higher for the P301S Tau protein compared to the wildtype. The ms7G6 antibody substantially reduced the aggregation of bothP301S Tau and wild-type Tau in vitro compared to IgG, as indicated bythe lower amount of fluorescence generated. This suggests that, even forthe P301S protein, ms7G6 binding to residues 362-366 alone could inhibitaggregation under these conditions.

Example 6: In Vitro Cell Seeding Model

To determine whether ms7G6 or a humanized version known as7G6-zuHC25-zuLC18 (see Example 10) had an effect on cells, each antibodywas tested in an in vitro cell-based model of Tau seeding andaggregation.

The 2N4R isoform of human wild type Tau was expressed in E. coli andthen purified as previously described (Soeda et al., Nat Commun. 2015,6: 10216). Recombinant Tau (40 μM) was mixed with heparin (240 μg/mL)and incubated at 37° C. for 48 to 96 hours in 100 mM sodium acetate, pH7.0, containing 2 mM DTT. Aggregated Tau protein was collected byultracentrifugation and resuspended in 100 mM sodium acetate pH 7.0 orPBS. The solution was then sonicated to produce the recombinant Tauseeds.

Neuro-2a (ATCC) cells were transfected in suspension with cDNAexpression plasmids encoding 0N4R P301S Tau using Lipofectamine LTX(Thermo Fisher Scientific) and plated at a density of 1.5×10 4 cells perwell into a 96-well plate in DMEM medium containing 10% fetal bovineserum. Cells were left to attach overnight at 37° C. prior to adding Tauseeds. In parallel, various concentrations of anti-Tau antibodies weremixed with 1 μg/mL of Tau seed and were also incubated overnight at 37°C. The following day, culture medium was removed and medium containingthe mixture of anti-Tau antibodies and seed were added. Plates werecultured again overnight at 37° C.

Cells were fixed with a final concentration of 4% paraformaldehyde andimmunostained by H-150 (Santa Cruz Technology, sc-5587), thioflavin S(Sigma-Aldrich, T-1892) and DAPI (Wako, 340-07971). Images were capturedand analysed using the InCell Analyzer 2200 and Toolbox.

As shown in FIGS. 6A, 6B, 6C, and 6D, a significant decrease inThioflavin S staining (aggregated Tau) was observed in response to bothms7G6 and 7G6-HCzu25-LCzu18 treatment. This indicates that bothantibodies were able to block the Tau seeding effect in this cell-basedmodel under these assay conditions.

Example 7: Efficacy in a Preclinical In Vivo Model of Tauopathy byPre-Incubating Recombinant P301S Tau Seeds with Antibodies

The effects of three new antibodies, including ms7G6, were tested in ashort term in vivo model of Tau deposition by pre-incubating therelevant antibodies with recombinant P301S Tau seeds. The seeds with orwithout antibody were then injected into the brains of P301S transgenicmice.

Intracerebroventricular (ICV) Injection of Tau Seeds

Pre-formed fibrillar (PFF) Tau was generated by mixing recombinant 2N4RP301S Tau (40 μM) and heparin (240 μg/mL), followed by an incubationstep at 37° C. for 48 to 96 hours in 100 mM sodium acetate, pH7.0,containing 2 mM DTT. Aggregated Tau was collected by ultracentrifugationand resuspended in 100 mM sodium acetate, pH7.0. The resulting fibrilswere sonicated and used as seeds for injection. Tau seeds at aconcentration of mg/mL were incubated with 1 mg/mL IgG₁ or 2 mg/mLanti-Tau antibody for 1 hour at 37° C. The Tau seeds/antibody mixtures,controls (i.e., Tau alone) or vehicle was injected into theintracerebroventricular (ICV) zone of 2-3.5 months old P301S transgenicmice (MRC Technology, United Kingdom). These mice overexpress human 0N4RP301S Tau under the control of the murine neuron-specific Thy-1 promoteron a CBA×C57/b16 background.

It has been reported previously that these animals, if untreated,develop widespread Tau pathology in the brain and spinal cord withsignificant motor deficits at 5 to 6 months of age (Allen et al., JNeurosci. 2002, 22(21):9340-51). In the current experiment using youngerP301S mice, animals were sacrificed two weeks after the ICV injection,brains were removed, and the tissue region of interest collected. Tissuesamples were then fractionated into sarkosyl-soluble and insoluble Tau(Sahara et al., J Neurochem. 2002 December; 83(6):1498-508) as describedbelow.

Extraction of Sarkosyl-Insoluble Tau from Seed-Injected P301S MouseBrain

Tissue was homogenized in 19 volumes (tissue weight/volume) ofextraction buffer containing 50 mM Tris-HCl (pH7.5) (Invitrogen), 5 mMEDTA (Nippon Gene), 1 mM EGTA (Nacalai Tesque), 1% NP-40 (Fluka), 0.25%deoxycholic acid sodium salt (Sigma Aldrich), 0.1 M NaCl, 0.5 mM PMSF(Sigma Aldrich), 1× PhosSTOP™ (Roche, Basel, Schweiz), and 1× CompleteEDTA(−) (Roche). Homogenates were centrifuged at 163,000 g at 4° C. for20 minutes and the resulting supernatants were collected and retained asthe Tris buffer-soluble fraction. The pellet was resuspended in about 10volumes (tissue weight/volume) of buffer containing 10 mM Tris-HCl(pH7.5), 0.5 M NaCl, 1 mM EGTA, 10% sucrose (Wako Pure Chemical), and 1%sarkosyl prior to sonication. Sarkosyl-treated samples were incubated at37° C. for 60 minutes, and then centrifuged at 163,000 g at 4° C. for afurther 20 minutes. The supernatants were collected as thesarkosyl-soluble fraction. Finally, about 10 volumes of PBS (Gibco) wasadded to the pellet which was then sonicated. This formed thesarkosyl-insoluble fraction.

Detection of Sarkosyl-Insoluble Tau by Western Blotting

Sarkosyl-insoluble fractions were solubilized in NuPAGE™ LDS samplebuffer and NuPAGE™ sample reducing agent (Invitrogen), heated at 70° C.for 10 minutes, and separated using 12.5% polyacrylamide gels (DRC).Proteins were transferred to 0.2 μm PVDF membranes (Bio-Rad, Hercules,CA, USA) and blots were blocked in 2.5% skimmed milk (Yukikirushi) inTBS (Takara) containing 0.05% Tween (Nacalai tesque) for 1 hour at roomtemperature. After blocking, blots were probed with the human-specificmonoclonal anti-Tau antibody HT7 (1:1000 or 1:2000, Thermo FisherScientific, Waltham, MA, USA) in blocking buffer for 1 hour at roomtemperature. The blots were washed in TB S-T for 30 minutes and thenincubated with HRP-conjugated anti-mouse IgG (1:2000, GE healthcare) fora further 1 hour at room temperature. Secondary antibody was removed andblots were washed as described above. Tau proteins were detected bychemiluminescent horseradish peroxidase (HRP) substrate (MerckMillipore) and quantified using the Fusion FX (Vilber-Lourmat, France)analyzer. To determine the amount of Tau, serial dilutions of standardsTau derived from the originating sarkosyl-insoluble fraction of P301Sspinal cord were loaded onto each gel.

As shown in FIG. 7 , pre-incubation of P301S seeds with ms7G6 but notcontrol IgG, 8E5 or 1F1 showed a significant decrease insarkosyl-insoluble Tau levels compared with vehicle. This suggested thatms7G6 was a superior antibody in this paradigm compared to the otheranti-Tau antibodies generated.

Example 8: Validation of the P301S Seeding and Transmission In VivoModel

To determine whether any transmission from one brain region to anotherof pathological Tau could occur in a rodent preclinical model, the sameseeding experiment was performed in P301S transgenic mice as describedin Example 7 but with some modifications. In this case, 20 μL ofrecombinant P301S Tau seeds at a concentration of 0.9 mg/mL was injectedICV into the brains of 2.5 to 3 month old mice. Mice were sacrificed ateither 2, 4 or 6 weeks following the initial seed injection, brains wereremoved and both hippocampus and cortex were retained. Thesarkosyl-insoluble Tau was prepared and detected as described above.

As shown in FIG. 8 , a sharp increase in insoluble Tau levels wasobserved in the hippocampus between 2 and 4 weeks post seed-injectionbut only low levels of insoluble Tau was observed in the cortex at thesame time point. However, between 4 and 6 weeks following seed injectiona greater increase of insoluble Tau was observed in the cortex comparedwith the no-seed control group. This shows that, in this model,insoluble Tau can form in the hippocampus, prior to the cortex,suggestive of a secondary transmission event.

Example 9: Effect of Peripheral Once Weekly Dosing of 7G6 in the P301SSeed Injection In Vivo Model a) Experiment 1

The P301S Tau seed injection into P301S transgenic mice was performed asdescribed in Example 8 with minor modifications. About seven to aboutfour hours prior to Tau seed injection, mice received a dose of either40 mg/kg IgG2b control antibody (BioXCell) or ms7G6 antibodyintraperitoneally. Each antibody was formulated in 25 mM phosphatebuffer (pH6.5) with 150 mM NaCl. A vehicle treatment control group wasalso included which received buffer alone. Following Tau seed injectioninto the brain, mice received further doses of antibody or buffer onceweekly for a period of 6 weeks. Animals were then sacrificed, braintissues isolated, and insoluble Tau was prepared and measured asdescribed in Example 7.

b) Experiment 2

An exact repeat of Experiment 1 (Example 9a) was performed.

c) Experiment 3

A repeat of Experiment 1 (Example 9a) was performed again except twodosing levels of ms7G6, 20 and 40 mg/kg, were administered and theanimals were sacrificed 8 weeks after seed injection rather than 6 weeksas in the previous two experiments.

As shown in FIGS. 9 and 10 , these three experiments demonstrate thatms7G6 can cause a reduction in insoluble Tau levels in this seedinjection model with P301S recombinant Tau seeds in a P301S transgenicmouse. The reduction observed in the cortex suggests that the antibodymay slow pathological Tau transmission. It was ascertained in example 4that the ms7G6 antibody is unable to bind to the HVSGG sequence (SEQ IDNO: 184) (aa299-303) that is present in the P301S site of the mutantprotein. Taken together, this means that the in vivo effects of ms7G6 inthis in vivo model are driven by the binding to Tau at the remainingHVPGG (SEQ ID NO: 79) epitope within the fourth repeat region(aa362-366).

Example 10: Antibody Humanization 10A. Materials & Methods

10A.a. In Silico Modeling

Discovery Studio 4.5 was used to generate a molecular model of the ms7G6Fv region. The top 1 to 3 crystal structures with the most homologousprotein sequences to the ms7G6 variable heavy (VH) and variable kappa(VK) domains were used as a template for generating twenty-five homologymodels using the “Create Homology Models” function. The model with thelowest energy score was selected and the energy was first minimized forjust the hydrogens and then for all atoms. Framework residues differingbetween the mouse sequences (HCzu1 and LCzu1) were highlighted and thoseclosest to the CDRs or at the VH/VK interface were identified asresidues that may be important for maintaining Tau binding by the CDRsor for antibody stability, respectively. CDR residues differing betweenthe mouse sequences (HCzu1 and LCzu1) were highlighted and residues wereidentified that may be not important for maintaining Tau binding by theCDRs.

10A.b. Gene Synthesis and Cloning

10A.b.1. InFusion™ Cloning

Humanized heavy and light variable domains were codon-optimized forexpression in CHO cells and were synthesized by GeneArt. The variabledomains were synthesized with a Kozak translation initiation sequenceand an Ig secretion leader sequence and included 15 base-pairs at the 5′and 3′ ends homologous to the cloning site within the subcloning vector.PCR fragments synthesized by GeneArt were subcloned into an expressionplasmid containing a human gamma or kappa constant region using anInFusion™ HD cloning kit (Clontech). All clones were sequenced toconfirm the presence and fidelity of the inserts.

10A.b.2. QuikChange™

Point mutations were made using Stratagene's QuikChange™ XL according tothe manufacturer's protocol. All clones were sequenced to confirm thepresence of the mutation.

10A.c. Cell Culture

10A.c.1. HEK Transient mAb Production

For each milliliter of 3×10⁶ cells to be transfected with ExpiFectamine™(Thermo), 333.3 ng HC plasmid and 333.3 ng LC plasmid were incubated for5-10 min in 50 μL Opti-MEM (Thermo). Likewise, 2.67 μL ExpiFectamine™was incubated in 50 μL Opti-MEM. The ExpiFectamine™ solution was addedto the DNA mixture and incubated for 20-30 min at room temperature. TheDNA:ExpiFectamine™ mixture was added to the cells while swirling andincubated at 37° C., 8% CO₂, shaking at 125 rpm. The following day, 5 μLof enhancer 1 and 50 μL of enhancer 2 per mL of cells were added to thetransfection with continued incubation for another 7-10 days. After48-72 h, cells were fed at a final concentration of 10 g/L Yeastolate(BD Biosciences), 5 mM valeric acid (Sigma-Aldrich), and 1:100 CD LipidConcentrate (Thermo).

10A.c.2. CHO Transient mAb Production

For each milliliter of 6×10⁶ cells to be transfected with ExpiFectamine™CHO (Thermo), 500 ng HC plasmid and 500 ng LC plasmid was mixed inOpti-PRO™ (Thermo) in μL total volume. Likewise, 3.2 μL ExpiFectamine™CHO was mixed in 36.8 μL Opti-PRO. The ExpiFectamine™ CHO solution wasadded to the DNA mixture and incubated for 1-5 min at room temperature.The DNA:ExpiFectamine™ CHO mixture was added to the cells while swirlingand incubated at 37° C., 8% CO₂, shaking at 125 rpm. The following day,6 μL of enhancer and 160 μL of feed per mL of cells were added to thetransfection, and cells were transferred to 32° C., 5% CO₂. At day 5, anadditional 160 μL of feed per mL of cells was added. At day 12 to 14,the supernatants were harvested.

10A.d. MAb Purification

10A.d.1. Batch Purification

Prosep™-vA High Capacity Protein A resin (Millipore) or CaptureSelect™KappaSelect LC-kappa resin (Thermo) was equilibrated with DPBS, and 50μL were added to 2 mL of sample. Following incubation at roomtemperature for 1 hour, the medium and resin were added to a filterplate and washed twice with 1 mL DPBS. The sample was eluted from theresin by addition of 400 μL 0.1 M Glycine, pH 2.9 followed bycentrifugation at 15,000×g for 30 s. The sample was neutralized with 20μL of 1 M Tris, pH 8.0. The samples were concentrated to 100 μL bycentrifugation at 15,000×g for 5 minutes using 0.5 mL Amicon™ Ultra, 10k cutoff filters (Millipore) and were buffer-exchanged into DPBS using0.5 mL Zeba™ desalting columns, 7K MWCO, according to the manufacturer'sprotocol.

10A.d.2. Column Purification

Purification was performed using an AKTA Xpress purification platform(GE Healthcare). Up to 1 L conditioned medium was loaded onto a 5 mLMabSelect™ SURE column (GE Healthcare) equilibrated in 20 mM sodiumphosphate, 150 mM NaCl, pH 7.0. The column was washed extensively withequilibration buffer following loading until a stable baseline wasobserved. Bound material was eluted using 100 mM glycine, pH 2.9. Elutedmaterial was immediately injected on to a 26/10 HiPrep desalting column(GE Healthcare) equilibrated in 1× phosphate-buffered saline (PBS) andeluted in the same buffer. Peak fractions were pooled. The material wasanalyzed for protein content by BCA assay (Thermo) and purity byreducing and non-reducing SDS-PAGE.

10A.e. 2N4R Tau-binding ELISA

A black Nunc MaxiSorp 96-well plate was coated with 2 μg/mL (unlessotherwise indicated) of recombinant wild-type 2N4R Tau in DPBS overnightat 4° C. The following day the plate was aspirated and washed threetimes with Wash Buffer (PBS+0.05% Tween-20). The wells were incubatedwith Assay Buffer (1% w/v BSA [heat shock fraction, Sigma], 0.05%Tween-20 [BioRad], DPBS) for 1 h at room temperature. The Assay Bufferwas aspirated and the wells were washed three times as above. Variousconcentrations of mAbs in DPBS were added to each well for 1 hour atroom temperature while shaking on a microtiter plate shaker. Sampleswere aspirated and the wells were washed three times as above.HRP-conjugated goat anti-mouse IgG (H+L) (JIRL 115-035-146), gt anti-huIgG (H+L) (JIRL 109-035-127), or Streptavidin-HRP (JIRL 016-030-084) wasdiluted 1:5000 in Assay Buffer and added to the wells. Followingincubation and shaking at room temperature for 1 hour, samples wereaspirated and the wells were washed three times as above. QuantaBlu(Thermo) was added to each well and incubated for 15 min at roomtemperature. The relative fluorescence units (RFU) were measured withthe excitation and emission wavelengths set at 320 and 460 nm,respectively, using a Spectramax™ M5 plate reader (Molecular Devices).

10A.f. Surface Plasmon Resonance (SPR) Binding Analyses

10A.f.1. Anti-Human/Anti-Mouse Capture Monomeric Tau-Binding Assay

10A.f.1.i. Chip Preparation

All experiments were performed using a BIAcore™ T-100 instrument (GEHealthcare). 10 μL anti-human IgG (monoclonal mouse anti-human Fc) fromhuman antibody capture kit (GE Healthcare) was diluted to 25 μL/mL in200 μL final immobilization buffer (10 mM sodium acetate, pH 5.0). Theflow rate was set to 5 flowpath 1. Fifty μL N-hydroxysuccinamide (NETS)and 50 μL 1-ethyl-3-(3-dimethylaminopropyl) carbidiimide (EDC) weremixed and injected for 420 sec to activate the CM5 chip surface. Thediluted antibody was injected for 360 seconds followed by 1 Methanolamine for 420 seconds. The flowpath was then switched to flowpath2. A new EDC/NHS mixture was prepared and the procedure was repeated forflow cell 2. The surface was conditioned by 2 injections of 30 sec usingflowpath 1,2 at 30 μL/min of 3M MgCl₂. For the anti-mouse surface, 10 μLanti-mouse IgG (polyclonal rabbit anti-mouse IgG) from mouse antibodycapture kit (GE Healthcare) was diluted to 30 μL/mL in 324 μL finalimmobilization buffer (10 mM sodium acetate, pH 5.0). The flow rate wasset to 5 μL/min, flowpath 3. Fifty μL NHS and 50 μL EDC were mixed andinjected for 420 sec to activate the chip surface. The diluted antibodywas injected for 420 sec. 1 M ethanolamine was injected for 420 sec.Flow path was switched to flowpath 4. A new EDC/NHS mixture was preparedand the procedure was repeated for flow cell 4. The surface wasconditioned by 2 injections of 30 sec using flowpath 3,4 at 30 μL/min of10 mM glycine, pH 1.7.

-   -   Final immobilization levels were:    -   Flow cell 1—10,000 RU (anti-human)    -   Flow cell 2—10,092 RU (anti-human)    -   Flow cell 3—11,824 RU (anti-mouse)    -   Flow cell 4—11,216 RU (anti-mouse)

10A.f.1.ii. Binding Assay

The running buffer used for the binding assay was PBS-P+/0.2% BSA. Allantibodies were diluted to 1 μg/mL in PBS-P+/0.2% BSA (same preparationas used for running buffer), centrifuged at 14,000 g for 5 min at roomtemperature, and the supernatant was transferred to a new tube. Analyte(Tau monomer 2N4R wt, 2.15 mg/mL, 47 μM) was diluted to 100 nM inPBS-P+/0.2% BSA, centrifuged at 14,000 g for 5 min at room temperature,and the supernatant transferred to a new tube. 100 nM solution wasserially-diluted 5-fold into PBS-P+/0.2% BSA. Final concentrations were100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0 nM. Humanizedantibodies were captured on flow cell 2 at a flow rate of 10 μL/min fora contact time of 60 sec. Murine antibodies were captured on flow cell 4at a flow rate of 10 μL/min for a contact time of 60 sec. Dilutions ofTau protein were injected over all 4 flow cells at a flow rate of 30μL/min for a contact time of 240 sec. Dissociation was followed for 900sec. Following each cycle, surface was regenerated by a 30 sec injection(flowpath 1,2) at 30 μL/min of 3M MgCl₂, a 30 sec injection (flowpath3,4) at 30 μL/min of 10 mM glycine, pH 1.7, a 30 sec injection (flowpath1,2) at 30 μL/min of 3 M MgCl₂, followed by two 30-sec injections(flowpath 3,4) at 30 μL/min of 10 mM glycine, pH 1.7. After the run,data collected was fitted to a steady-state binding model using allconcentrations using BIAEvaluations. Kinetic data fitting was performedusing a 1:1 Langmuir model, excluding the 100 nM trace (inclusion of 100nM trace resulted in unacceptably high X² values). A subset of antibodybinding data was also analyzed using a 2-state model.

10A.f.2. Anti-Human Capture Monomeric Tau-Binding Assay

10A.f.2.i. Chip Preparation

Chip preparation was performed using a BIAcore™ T-100 instrument. Chippreparation was performed using the method wizard for immobilization.Running buffer was HBS-P+. Fifteen μL anti-human IgG (monoclonal mouseanti-human Fc) from human antibody capture kit (GE Healthcare) wasdiluted to 25 μL/mL in 300 μL final immobilization buffer (10 mM sodiumacetate, pH 5.0). The flow rate was set to 5 μL/min. Immobilization wasperformed on all four flow cells with a ligand contact time of 360 sec.The surface was conditioned by two injections of 30 sec using flowpath1,2, 3, 4 at 30 μL/min of 3 M MgCl₂.

-   -   Final immobilization levels were:    -   Flow cell 1—7341 RU    -   Flow cell 2—7683 RU    -   Flow cell 3—7530 RU    -   Flow cell 4—6303 RU

10A.f.2.ii. Binding Assay

Binding experiments were performed using a BIOcore™ T-100 instrument ora T-200 instrument. Running buffer used for the binding assay wasPBS-P+/0.2% BSA. All antibodies were diluted to 2 μg/mL in PBS-P+/0.2%BSA (the same preparation as used for the running buffer), centrifugedat 14,000 g for 5 min at room temperature, and the supernatanttransferred to new tube. Analyte (Tau monomer 2N4R wt, 2.15 mg/mL, 47μM) was diluted to 100 nM in PBS-P+/0.2% BSA, centrifuged at 14,000 gfor 5 min at room temperature, and the supernatant transferred to a newtube. 100 nM solution was serially-diluted 5-fold into PBS-P+/0.2% BSA.Final concentrations were 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032nM, and 0 nM. Humanized antibodies were captured on flow cells 2, 3, and4 sequentially at a flow rate of 10 μL/min for a contact time of 60 sec.Dilutions of Tau protein were injected over all 4 flow cells at a flowrate of 30 μL/min for a contact time of 240 sec. Dissociation wasfollowed for 900 sec. Following each cycle, the surface was regeneratedby two sequential injections of sec at 30 μL/min of 3 M MgCl₂ over allfour flow cells. After the run, kinetic data fitting was performed usinga 1:1 Langmuir model, excluding the 100 nM trace (inclusion of 100 nMtrace resulted in unacceptably high X² values).

10A.f.3. Streptavidin Capture Monomeric Tau-Binding Assay

10A.f.3.i. Antibody Preparation

400 μg of each antibody was diluted to 2 mg/mL and buffer-exchanged into0.1 M sodium bicarbonate, pH 8.3 using 0.5 mL Zeba™ 40 kDa MWCOdesalting columns (Thermo). NHS-PEG4-biotin, prepared immediately beforeuse by dissolving in water to a 20 mM final stock concentration, wasadded to antibodies at a 5:1 molar ratio (biotin:MAb) and conjugated for1 hr at room temperature. Excess biotin was removed by two sequentialbuffer exchanges into 1×DPBS using 0.5 mL Zeba™ 40 kDa MWCO desaltingcolumns. For the BIAcore™ assay, antibodies were diluted to 2 μg/mL inPBS-P+/0.2% BSA (the same preparation used for the running buffer),centrifuged at 14,000 g for 5 min at room temperature, and thesupernatant transferred to a new tube. Injection time was subsequentlydetermined for each antibody to achieve a capture level of ˜225 RU.

Wild-type 2N4R Tau protein (2.15 mg/mL, 47 μM) was diluted to 100 nM inPBS-P+/0.2% BSA, centrifuged at 14,000 g for 5 min at room temperature,and supernatant transferred to a new tube. 20 nM solution wasserially-diluted 5-fold into PBS-P+/0.2% BSA. Final concentrations were20 nM, 4 nM, 0.8 nM, 0.16 nM, and 0 nM.

10A.f.3.ii. Binding Assay

The biosensor chip used was a CAP chip from the biotin CAPture™ kit (GEHealthcare, cat 28-9202-34). All experiments were performed using aT-100 instrument. CAP reagent was immobilized on all four flow cells(flowpath 1, 2, 3, 4) at a flow rate of 2 μL/min for 5 min (finalstreptavidin level was ˜3500 RU). Biotinylated humanized antibodies,biotinylated chimeric 7G6, or biotinylated murine ms7G6 were captured onflow cells 2, 3, and 4 sequentially at a flow rate of 10 μL/min for acontact time of 80 sec to 146 sec (biotinylated chimeric antibodycontact time was 240 sec). Dilutions of Tau protein were injected overall four flow cells at a flow rate of 30 μL/min for a contact time of180 sec in sequence from 0 nM to 20 nM. Following the last injection (20nM Tau), dissociation was followed for 900 sec. After each cycle, thesurface was regenerated by one injection of 120 sec 10 μL/min of 6 MGuanidine HCl, M NaOH over all four flow cells. Samples were assayed induplicate, except for murine 7G6 and 7G6-zuHC25-zuLC18, which wereanalyzed in duplicate on two separate flow cells (total of 4 analysesfor each). After the run, kinetic data fitting was performed using a 1:1Langmuir model using single cycle kinetics.

10A.g. Size Exclusion Chromatography-High Performance LiquidChromatography (SEC-HPLC)

SEC-HPLC was performed on an Agilent 1260 quaternary pump HPLC systemequipped with an AdvanceBio™ SEC 300A, 2.7 μm, 4.6 mm ID×50 mm guardcolumn, and AdvanceBio™ SEC 300A, 2.7 μm, 4.6 mm ID×300 mm column(Agilent). The isocratic flow of a mobile phase consisting of 0.1 Msodium phosphate (pH 6.5) was at 0.35 mL/min. The separation wasconducted at ambient temperature. The column effluent was monitored at280 nm. Fifty μg of sample (10 μL of 5 mg/mL sample) was injected foreach run; each sample was analyzed twice. Peak integration was performedusing Agilent OpenLAB software. Retention time, peak height, peak area,peak width, and peak symmetry were reported. The percentage ofaggregates and monomers were calculated based on the peak area.

10A.h. Differential Scanning Calorimetry (DSC) Analysis

VP Capillary Differential Scanning calorimeter (VP-CapDSC; MicroCal,VP-CapDSC, s/n 12-07-149 with Origin-7 graphing and MicroCalVP-Capillary DSC Software v.2.0) was used to decipher and compare thehigher order structure and thermal stability of various F(ab′)₂fragments and controls. Samples were allowed to acclimate to ambienttemperature for 30 minutes, followed by vortexing. The entire sample(0.4-0.5 mL) was added to appropriate wells of an assay plate(Microliter Analytical Supply, 96 well, 500 μL, round well and bottom,cat #07-2100; Sun Suri plate cover cat #300-005). 0.5 mL of 20% Contradsolution and 0.5 mL water were added to the appropriate wells of theassay plate. Sealed plates were placed into an auto-sampler at 10° C.

The run was programmed and initiated using the following assayparameters:

-   -   DSC Controls:    -   Start Temperature=25° C.    -   Final Temperature=100° C.    -   Scan Rate=100° C./Hr    -   Number of Rescans=0    -   Rescan Cooling Rate=EXP    -   Pre-scan Thermostat=10 Minutes    -   Post-scan Thermostat=5 Minutes    -   Post-Cycle Thermostat=25° C.    -   Filtering Period=10 Seconds    -   Autofill Cells at =30° C.    -   Feedback Mode/Gain=None    -   Unique Scans    -   Sample Parameters:    -   Concentration=mM    -   File Parameters=Auto #    -   Rinse Station=select Wash 2 (So will Wash 2 (1×PBS) then Wash 1        (Water))    -   Thermostat Control Set Point=25° C.    -   Pulse Control:    -   Pulse Size=−3    -   Duration=600    -   Pulse Off    -   Y-Axis Scale Units=mCal/Minute    -   Clean in-line with Contrad/Contrad at 25-70° C., 100° C./Hour        followed by two Buffer/Buffer injections.

10B. Results

10B.a. IGHV1/IGKV2 Humanization

10B.a.1. 7G6 in Silico Modelling

The human germline variable domain protein sequences most homologous tomouse ms7G6 mAb were retrieved using BLAST atwww_ncbi_nlm_nih_gov/igblast/andwww_imgt_org/3Dstructure-DB/cgi/DomainGapAlign_cgi. IGHV1-46*03 andIGKV2-30*02 variable domain families were the most homologous sequencesto ms7G6 (FIG. 11 ). Mouse framework sequences were replaced with theclosest homologous human germline sequences to generate CDR-graftedhumanized variants.

The mouse and CDR-grafted sequences were used to generate in silicomodels of the variable domains. The theoretical structure of the mouseand humanized models were superimposed, and residues in close proximityto the CDRs were analyzed for potential structural influence on theoverall structure of the CDR loops. While most of the differing residueswere not located at the dimer interface or were distal to the CDRs,several residues were found to be in close proximity (within 5 Å) of theCDRs.

In the Vκ domain, the hydroxyl group in mouse Tyr36 formed a potentialhydrogen bond with Trp100 in CDRH3. The human Phe36 loses this hydrogenbond, which may affect the structural integrity of CDRH3. Human Arg46 ismuch bulkier than the mouse Leu46, and Arg46 may sterically hinderproper folding of the CDRs. Similarly, in the Vh domain, position 71 waspositioned against the CDRs. The human Arg71 may sterically hinderproper folding of the CDRs compared to the mouse Va171. The human Va178was positioned similarly and is bulkier than the mouse Ala78. ThereforeVa178 may, but was unlikely to, affect the integrity of the CDRs.

The mouse ms7G6 antibody contained two unpaired cysteines that may beproblematic in the development of the mAb due to the presence of freethiols which could contribute to product aggregation, oxidation,cysteinylation, or glutathionylation. One Cys was located at position 57in CDRH2 and the second was at position 49 in FWRL2.

The Kabat definition of CDRH2 extends 8 C-terminal amino acids longerthan the IMGT definition. The latter 8 amino acids were analyzed fortheir proximity and potential contribution to antigen binding. Asn58 waswithin the potential antigen binding site at the potential CDR-antigeninterface at the top of the variable domains. Residues 60, 61, 64, and65 differing between mouse and the human germline sequence were outsideof the potential antigen binding site and were not likely to directlycontact the antigen or provide structural support for proper CDRfolding.

10B.a.2. Humanized Vh1 and Vid Variants and Analysis for Tau Binding byELISA

A series of humanized mutants were generated using the germline variabledomain Vh1 and Vκ2 families to evaluate the importance of mouse residuesat the positions predicted by in silico modeling to be important forCDR-antigen interactions (FIG. 12 ). Humanized and mouse 7G6 residueswere analyzed at Vh positions 60, 61, 64, 65, 71, and 78 in variouscombinations (7G6-HCzu1-4), as well as the C57S mutation (7G6-HCzu5).Combinations of human and mouse residues at positions 36, 46, and 49 inms7G6 Vκ were also analyzed (7G6-LCzu1-5) as well as the C49S mutation(7G6-LCzu6). MAbs were expressed in a matrix format whereby everycombination of humanized HCs and LCs were cotransfected, except7G6-HCzu5 was only coexpressed with 7G6-LCzu2 and 7G6-LCzu6 was onlycoexpressed with 7G6-HCzu3.

To test direct binding to Tau, 2N4R Tau was coated on 96-well plates andvarious concentrations of humanized mAbs were added to the wells. MAbsbound to Tau were detected with either an HRP-conjugated anti-mouseantibody (mouse [ms]7G6) or anti-human antibody (remaining samples).Samples were incubated for 1 h at room temperature in 96-well platescoated with 2N4R Tau. Following washing, HRP-conjugated anti-mouse oranti-human detection antibodies were added to the wells. The anti-mouseantibody was used to detect ms7G6. The amount of HRP activity in eachwell was measured by QuantaBlu fluorescent substrate and the RFUs weredetected by a SpectraMax M5 plate reader.

Data from the samples, grouped according to the LC variant, except thecysteine mutants which are grouped on the bottom-most graph, is shown inFIGS. 13A-13F. Amongst all of the 7G6 HC and LC variants, there waslittle difference in Tau binding (FIGS. 13A-F; Table 3). Although ms7G6showed better binding than the humanized variants, it should be notedthat this result may be misleading due to the differing detectionantibodies between the mouse and human samples. mAb2 corresponds tonon-Tau-binding control IgG antibody.

TABLE 3 EC50s* of humanized 7G6 Vh1/Vκ2 variants binding Tau Ab EC507G6-HCzu1-LCzu1 119.2 7G6-HCzu2-LCzu1 104.7 7G6-HCzu3-LCzu1 131.47G6-HCzu4-LCzu1 184.7 7G6-HCzu1-LCzu2 133.1 7G6-HCzu2-LCzu2 208.97G6-HCzu3-LCzu2 171.6 7G6-HCzu4-LCzu2 168.2 7G6-HCzu1-LCzu3 164.97G6-HCzu2-LCzu3 152.3 7G6-HCzu3-LCzu3 188.9 7G6-HCzu4-LCzu3 176.57G6-HCzu1-LCzu4 191.7 7G6-HCzu2-LCzu4 226.9 7G6-HCzu3-LCzu4 2537G6-HCzu4-LCzu4 282.6 7G6-HCzu1-LCzu5 167.1 7G6-HCzu2-LCzu5 186.97G6-HCzu3-LCzu5 183.6 7G6-HCzu4-LCzu5 199.4 7G6-HCzu5-LCzu2 1477G6-HCzu5-LCzu2 154.2 7G6-HCzu3-LCzu6 135 ms7G6 34.36 *The EC50s weredetermined by fitting a non-linear regression curve in GraphPad Prism6.05.

To reduce any potential immunogenicity, another series of mutants wasgenerated with increasing numbers of human residues (7G6-HCzu6, 7G6-HCzu7, and 7G6-HCzu 8; FIG. 12 ). Since Vh Ser57 showed little difference inbinding to Cys57, most of the mutants contained Ser57. To furtherconfirm that serine was a viable substitution for cysteine at position57, two mutant pairs differing at only position 57 were generated(7G6-HCzu7 and 7G6-HCzu9 and 7G6-HCzu8 and 7G6-HCzu10; FIG. 12 ).

All Vκ variants were engineered with Ser49, except 7G6-LCzu10 which wasmade to determine whether the human residue Tyr49 was a viablesubstitute for Cys49. 7G6-LCzu7 was analogous to 7G6-LCzu1 and 7G6-LCzu3except with Ser49. 7G6-LCzu21 was analogous to 7G6-LCzu5 and 7G6-LCzu22was analogous to 7G6-LCzu4, again with Ser49. 7G6-LCzu8 had a valine atposition 30 to determine whether the human residue at this positionretained Tau binding. Position 34 was somewhat buried in the structureand it was possible it did not contribute to antigen binding, thereforethe human residue Asn34 at the end of CDRL1 was engineered into7G6-LCzu9. All HC variants were coexpressed with 7G6-LCzu6 and all LCvariants were coexpressed with 7G6-HCzu5.

Tau binding was analyzed by a direct ELISA as above. Samples wereincubated for 1 hour at room temperature in 96-well plates coated withwild-type 2N4R Tau. After a wash step, HRP-conjugated anti-mouse oranti-human detection antibodies were added to the wells. The anti-mouseantibody was used to detect ms7G6. The amount of HRP activity in eachwell was measured by QuantaBlu fluorescent substrate and the RFUs weredetected by a SpectraMax M5 plate reader. A majority of the mAbs showedlittle difference in Tau binding in a direct ELISA assay (FIG. 14 ;Table 4). The notable exception was LCzu9 which exhibited no binding,even at the highest concentrations. Therefore, Vκ Glu34 was critical forantigen binding. In addition, LCzu22 showed reduced binding; Vκ Tyr36 incombination with Arg46 resulted in disruption of the antigen bindingsite.

TABLE 4 EC50s* of humanized 7G6 Vh1/Vκ2 variants binding Tau EC507G6-HCzu5-LCzu6 299.8 7G6-HCzu6-LCzu6 320.9 7G6-HCzu7-LCzu6 270.37G6-HCzu8-LCzu6 256.5 7G6-HCzu9-LCzu6 250.4 7G6-HCzu10-LCzu6 277.77G6-HCzu5-LCzu7 212.1 7G6-HCzu5-LCzu8 221 7G6-HCzu5-LCzu9 NB7G6-HCzu5-LCzu10 209.6 7G6-HCzu5-LCzu21 301.5 7G6-HCzu5-LCzu22 813.9ms7G6 86.33 *The EC50s were determined by fitting a non-linearregression curve in GraphPad Prism 6.05. NB (no binding) indicateslittle to no binding to Tau.

Binding of humanized and mouse antibodies were analyzed by surfaceplasmon resonance (BIAcore™) to determine their relative associationrates (k_(a)), dissociation rates (k_(d)), and equilibrium bindingconstants (K_(D)). Anti-mouse or anti-human antibodies were immobilizedon a CM5 chip and sample mAbs were captured on the chip. 2N4R Tau wasflowed over the chip and binding observed. The binding constants k_(a),k_(d), and K_(D) were determined using a 1:1 Langmuir fitting model.Antibody ms7G6 derived from hybridoma or IgG2a or IgG2b recombinantmaterial showed no difference in the association or dissociation rates(Table 5). Among the 7G6 HC variants, there were only slightdifferences, and the cysteine to serine mutations did not affect Taubinding. 7G6-LCzu2, LCzu6, LCzu7, LCzu8, and LCzu21 bound Tau similarly,demonstrating that the amino acids differing between these mAbs hadlittle impact on binding. The humanized samples demonstrated betterbinding to Tau than the mouse mAbs, but this was most likely due to thenecessity of using different capture antibodies in this assay format.

TABLE 5 BIAcore ™ analysis of mouse and humanized Vh1/Vκ2 Species/ k_(a)(×10⁵ k_(d) (×10⁻³ K_(D) MAb Isotype M⁻¹sec⁻¹) sec⁻¹) (nM)7G6-HCzu1-LCzu1 human/IgG1 25.70 0.519 0.202 7G6-HCzu2-LCzu1 human/IgG128.30 0.640 0.226 7G6-HCzu3-LCzu1 human/IgG1 27.70 0.856 0.3097G6-HCzu4-LCzu1 human/IgG1 35.70 0.847 0.237 7G6-HCzu1-LCzu2 human/IgG122.00 0.241 0.110 7G6-HCzu2-LCzu2 human/IgG1 21.20 0.214 0.1017G6-HCzu3-LCzu2 human/IgG1 20.00 0.242 0.121 7G6-HCzu4-LCzu2 human/IgG120.00 0.242 0.121 7G6-HCzu5-LCzu2 human/IgG1 18.60 0.237 0.1277G6-HCzu3-LCzu6 human/IgG1 19.00 0.227 0.120 7G6-HCzu5-LCzu6 human/IgG121.4 0.206 0.0961 7G6-HCzu6-LCzu6 human/IgG1 22.1 0.213 0.09617G6-HCzu7-LCzu6 human/IgG1 20.8 0.226 0.109 7G6-HCzu8-LCzu6 human/IgG121.7 0.21 0.0968 7G6-HCzu9-LCzu6 human/IgG1 20.6 0.193 0.09387G6-HCzu10-LCzu6 human/IgG1 19.8 0.213 0.108 7G6-HCzu5-LCzu7 human/IgG131.4 0.304 0.0968 7G6-HCzu5-LCzu8 human/IgG1 36 0.298 0.08287G6-HCzu5-LCzu9 human/IgG1 no binding no binding no binding7G6-HCzu5-LCzu10 human/IgG1 32.7 0.53 0.162 7G6-HCzu5-LCzu21 human/IgG129.3 0.278 0.095 7G6-HCzu5-LCzu22 human/IgG1 18.8 2.77 1.48 Hybridomams7G6 mouse/IgG2b 4.64 1.533 3.305 recombinant ms7G6 mouse/IgG2b 3.731.556 4.170 recombinant ms7G6 mouse/IgG2a 5.49 1.497 2.725

These data, along with the data from ELISA assay, demonstrated therequirement for 7G6 Vκ Glu34 and the detrimental combination of 7G6 VκTyr36 and Arg46. 7G6 Vκ residues Tyr36 and Leu46 in LCzu6 were slightlyfavored over the human Phe36 and Arg46 residues in 7G6-LCzu7 and7G6-LCzu8, but retaining the human residues at these positionsoutweighed the minor reduction in the k_(d). The human Vκ Tyr57 in7G6-LCzu10 had a significant impact on the k_(d).

10B.a.3. SDS-PAGE Analysis of HC/LC Stability for Vh1 and Vκ2 Variants

Two micrograms of each mAb were mixed with 4×NuPAGE™ LDS Sample Bufferand separated non-reduced on a 4-12% Bis-Tris SDS-PAGE gel in MOPSbuffer. Gels were stained with InstantBlue™ and destained in water. AllmAbs with Cys49 in the LC (7G6-LCzu2, 7G6-LCzu3, 7G6-LCzu4, and7G6-LCzu5) were not stable, and under non-reducing conditions, HC-HC-LCtrimers, HC-HC dimers, and free LC were separated by SDS-PAGE (FIG. 15). 7G6-LCzu2 had fewer lower molecular weight species, likely due tothis Vκ having two additional mouse residues, Tyr36 and Leu46,stabilizing the Vh-Vκ interaction. 7G6-LCzu3, 7G6-LCzu4, and 7G6-LCzu5had one or both of these residues changed to the human Phe36 and/orArg46. The least stable mAbs were the LCzu3 variants with both humanresidues. 7G6-LCzu7, 7G6-LCzu8, 7G6-LCzu9, and 7G6-LCzu22 had a smallamount of free light chain, suggesting the HC and LC interaction inthese samples may not be optimal, resulting in a small amount ofantibodies not forming the HC-LC interchain disulfide bond. As with7G6-LCzu3, these LC variants have human residues at one or bothpositions 36 and 46. 7G6-LCzu10 and 7G6-LCzu21 also have human residuesat these positions, but no free LC was seen, possibly a result ofincomplete staining by the InstantBlue™ stain.

10B.b IGHV3/IGKV1 Humanization 10B.b.1 Humanized Vh3 and Via Variantsand Analysis for Tau Binding by ELISA

The humanized 7G6 variants discussed above utilized the human germlinevariable domain families IGHV1 and IGKV2 chosen based on theirsimilarity to ms7G6. However, these families are underrepresented in thehuman population, thereby increasing the chance the humanized variantswould be immunogenic in patients (Brezinschek H P, Foster S J, Dörner T,Brezinschek R I, Lipsky P E. Pairing of variable heavy and variablekappa chains in individual naive and memory B cells. J Immunol. 1998 May15; 160(10):4762-7; Jayaram N, Bhowmick P, Martin A C. Germline Vh/VKpairing in antibodies. Protein Eng Des Sel. 2012 October; 25(10):523-9;Tiller T, Schuster I, Deppe D, Siegers K, Strohner R, Herrmann T,Berenguer M, Poujol D, Stehle J, Stark Y, HeBling M, Daubert D, FeldererK, Kaden S, Minn J, Enzelberger M, Urlinger S. A fully synthetic humanFab antibody library based on fixed Vh/VK framework pairings withfavorable biophysical properties. MAbs. 2013 May-June; 5(3):445-70).Therefore the ms7G6 CDRs were grafted onto the more common IGHV3 andIGKV1 families (FIG. 16 ).

The aforementioned in silico model of ms7G6 was analyzed as above forhuman residues in close proximity (5 Å) of the CDRs. Human residues inVh at positions 49, 71, 76, 78, and 94 and in Vκ at positions 2 and 57were identified as potential critical framework residues. Two humanizedvariants of the Vh and Vκ were generated, one with all human frameworkresidues (7G6-HCzu11; 7G6-LCzu11) and one with potentially criticalresidues back-mutated (7G6-HCzu12; 7G6-HCzu12) (FIG. 17 ). Both HCs werecoexpressed with both LCs.

2N4R Tau was coated on 96-well plates and various concentrations ofhumanized mAbs were added to the wells as above. MAbs bound to Tau weredetected with either an HRP-conjugated anti-mouse antibody (ms7G6) oranti-human antibody (remaining samples). All humanized mAbs boundsimilarly to Tau, but the 7G6-HCzu12-LCzu12 mAb had the lowest EC50(FIG. 18 & Table 6). Both mouse mAbs showed better binding than thehumanized variants, possibly due to the different detection antibodiesused between the mouse and human samples. These data suggest that atleast some of the human residues in proximity to the CDRs negativelyaffect antigen binding.

TABLE 6 EC50s of humanized 7G6Vh1/Vκ2 variants binding Tau Ab EC50 ms7G689.88 7G6-HCzu11-LCzu11 245.9 7G6-HCzu11-LCzu12 284.2 7G6-HCzu12-LCzu11218.4 7G6-HCzu12-LCzu12 153.4 The EC50s were determined by fitting anon-linear regression curve in GraphPad Prism 6.05.

To reduce potential immunogenicity, another series of mutants wasgenerated with increasing numbers human residues. Residues in theC-terminal half of CDRH2 had little impact on Tau binding in Vh1-basedvariant 7G6-HCzu4. Therefore, these residues were changed to the Vh3germline residues in 7G6-HCzu13, 7G6-HCzu14, 7G6-HCzu19 and 7G6-HCzu20(FIG. 17 ). Variants of 7G6-HCzu12 were made such that mouse residueswere replaced with human in order of probable increasing importance onantigen binding, based on the in silico ms7G6 model. For instance, thesidechain of Ser76 was on a loop facing away from the CDRs and was theleast likely residue to impact the CDR-antigen interaction. Therefore itwas the first residue to be changed to human residue Asn76 in7G6-HCzu15. Residue 49 was mutated next (7G6-HCzu16), then 78(7G6-HCzu17), 71 (7G6-HCzu18), and finally 94 (7G6-HCzu20).

With little difference between 7G6-LCzu11 and 7G6-LCzu12, it wasexpected that human residues at positions 2 and 57 would have littleimpact on antigen binding. Therefore, each of these was mutated one at atime. For position 57, tyrosine and serine substitutions were analyzed.A valine at position 30 was introduced in 7G6-LCzu16 and 7G6-LCzu17. Thehuman residue Asn34 at the end of CDRL1 was engineered into 7G6-LCzu17.All HC variants were coexpressed with 7G6-LCzu12 and all LC variantswere coexpressed with 7G6-HCzu12.

A majority of the mAbs showed little difference in Tau binding in adirect ELISA assay (FIG. 19 & Table 7). The notable exception was LCzu17which exhibited no binding, even at the highest concentrations.Therefore, Vκ Glu34 was critical for antigen binding.

TABLE 7 EC50s of humanized 7G6Vh1/Vκ2 variants binding Tau Ab EC507G6-HCzu12-LCzu12 283.4 7G6-HCzu13-LCzu12 320.1 7G6-HCzu14-LCzu12 335.17G6-HCzu15-LCzu12 358 7G6-HCzu16-LCzu12 313.1 7G6-HCzu17-LCzu12 341.67G6-HCzu18-LCzu12 278.4 7G6-HCzu19-LCzu12 216.4 7G6-HCzu20-LCzu12 317.27G6-HCzu12-LCzu13 263.3 7G6-HCzu12-LCzu14 248.6 7G6-HCzu12-LCzu15 287.67G6-HCzu12-LCzu16 328.8 7G6-HCzu12-LCzu17 NB ms7G6 86.33 The EC50s weredetermined by fitting a non-linear regression curve in GraphPad Prism6.05. NB (no binding) indicates little to no binding to Tau. 10B.b.2BIAcore ™ analysis of Tau affinity for Vh3 and Vκ1 variants

Binding of humanized and mouse antibodies were analyzed by BIAcore™ todetermine their relative association rates (ka), dissociation rates(kd), and equilibrium binding constants (K_(D)). Anti-mouse oranti-human antibodies were immobilized on a CM5 chip and sample mAbswere captured on the chip. 2N4R Tau was flowed over the chip and bindingobserved. The binding constants k_(a), k_(d), and K_(D) were determinedusing a 1:1 Langmuir fitting model. Both 7G6-HCzu12-based mAbs hadsimilar k_(a) and k_(d) values (Table 8). However, the k_(a) of7G6-HCzu11 was decreased, though the k_(d) was unaffected. Therefore,human residues in the Vh3 framework impact binding to Tau. As with theELISA assay, 7G6-LCzu17 did not bind Tau. The difference in k_(d)between 7G6-HCzu12, 7G6-HCzu13, and 7G6-HCzu14 suggests the CDRH2C-terminal human residues have a negative impact on antigen binding. Thedecrease in k_(d) was not observed for 7G6-HCzu19 and 7G6-HCzu20 whichalso have human residues in the region; however, these mAbs had adecrease in k_(a). 7G6-HCzu15 did not bind to the chip very well, andthe data from this mAb were questionable. While no specific data on thesingle S76N mutation was available, the k_(a) and k_(d) values for7G6-HCzu16, 7G6-HCzu17, 7G6-HCzu18 were similar to 7G6-HCzu12 suggestingthe S76N mutation should not affect Tau binding. The k_(a) for7G6-HCzu20 was less than 7G6-HCzu19 and may be a result of the K94Rmutation. Therefore human residues at position 49, 71, 76, and 78 didnot appear to affect Tau binding. The humanized samples demonstratedbetter binding to Tau than the mouse mAbs, but this was most likely dueto the necessity of using different capture antibodies in this assayformat.

TABLE 8 BIAcore ™ analysis of mouse and humanized 7G6 Vh3/Vκ1 mAbsSpecies/ k_(a) (×10⁵ k_(d) (×10⁻³ K_(D) MAb Isotype M⁻¹sec⁻¹) sec⁻¹)(nM) 7G6-HCzu11-LCzu11 human/IgG1 8.53 0.175 0.205 7G6-HCzu12-LCzu11human/IgG1 13.80 0.181 0.132 7G6-HCzu12-LCzu12 human/IgG1 14.90 0.1930.129 7G6-HCzu12-LCzu12 human/IgG1 17.2 0.151 0.0875 7G6-HCzu13-LCzu12human/IgG1 14.2 0.239 0.168 7G6-HCzu14-LCzu12 human/IgG1 14.6 0.1940.133 7G6-HCzu15-LCzu12 human/IgG1 20.2 0.278 0.138 7G6-HCzu16-LCzu12human/IgG1 15.3 0.174 0.114 7G6-HCzu17-LCzu12 human/IgG1 17 0.124 0.0737G6-HCzu18-LCzu12 human/IgG1 15.7 0.128 0.0815 7G6-HCzu19-LCzu12human/IgG1 12.5 0.152 0.121 7G6-HCzu20-LCzu12 human/IgG1 11.4 0.1360.119 7G6-HCzu12-LCzu13 human/IgG1 14 0.124 0.0888 7G6-HCzu12-LCzu14human/IgG1 17.3 0.119 0.0689 7G6-HCzu12-LCzu15 human/IgG1 14.7 0.1410.0959 7G6-HCzu12-LCzu16 human/IgG1 14.9 0.148 0.099 7G6-HCzu12-LCzu17human/IgG1 no binding no binding no binding Hybridoma ms7G6 mouse/IgG2b4.64 1.533 3.305 recombinant ms7G6 mouse/IgG2b 3.73 1.556 4.170recombinant ms7G6 mouse/IgG2a 5.49 1.497 2.725

There was little difference between the k_(a) or k_(d). values for any7G6 LC variant, except 7G6-LCzu17, which did not bind Tau due to Asn34.Therefore, the human Ile2 had no effect on antigen binding. Cysteine,serine, and tyrosine all appeared to be tolerated at position 57. Avaline at position 30 had no impact on Tau binding.

10B.b.3 SDS-PAGE Analysis of HC/LC Stability for Vh3 and Via Variants

Two micrograms of each mAb were mixed with 4×NuPAGE™ LDS Sample Bufferand separated non-reduced on a 4-12% Bis-Tris SDS-PAGE gel in MOPSbuffer. Gels were stained with InstantBlue and destained in water. Themore human 7G6-HCzu11, especially when paired with the less human7G6-LCzu12, resulted in HC-LC dimers and free HC (FIG. 20A). Further,7G6-HCzu18 and 7G6-HCzu19 showed significant fragments (FIGS. 20B and20C). These two antibodies differ from the others at position 71.Therefore, the human residue Arg41, while not impacting Tau binding,contributed to destabilization of the HC-LC interaction. All LC variantsshowed no antibody fragments. Contrary to Vh1-Vκ2 mAbs analyzed above,Cys49 did not produce HC-HC-LC trimers, HC-HC dimers, or free LC.

10B.c. Screening of Humanized Antibodies

Based on human-ness of the sequences, BIAcore™ affinity data andSDS-PAGE stability data from the IGHV1/IGKV2 humanization, 7G6-HCzu8 waschosen as the most human sequence with the highest affinity for Tau.7G6-LCzu6 and 7G6-LCzu21 had comparable stability in SDS-PAGE andaffinity for Tau but differed by one amino acid at position 36. Bothlight chains were chosen to be coexpressed with 7G6-HCzu8 to determinethe best IGHV1/IGKV2-based mAb.

Another round of mutagenesis was performed on the most human, highestaffinity, and most stable IGHV3 and IGKV1 variants to remove theunpaired cysteines at position 57 and 49, respectively. 7G6-HCzu17 and7G6-HCzu18 were chosen as the most human framework residues with thehighest affinity. 7G6-HCzu18 was super-humanized by introducing humanresidues into the C-terminal portion of CDRH2 to generate 7G6-HCzu21,but the affinity was never analyzed. 7G6-HCzu18, 7G6-HCzu21, and7G6-HCzu17 all contained a cysteine at position 57, and a serine wasintroduced at position 57 in all three variants to generate 7G6-HCzu24,7G6-HCzu23, and 7G6-HCzu25, respectively (FIG. 17 ). 7G6-LCzu14 and7G6-LCzu15 were the most human Vκ sequences with the highest affinity.7G6-LCzu14 retained Cys49 and was therefore mutated to remove theunpaired cysteine and was named 7G6-LCzu18. Each IGHV3 HC was pairedwith each IGKV1 LC.

10B.c.1 Intact Mass Analysis

The mass of each mAb was analyzed by ESI-MS to confirm the theoreticalmass matched the observed mass. MAbs were digested with IdeS to generateF(ab′)2 fragments, followed by reduction with 2 mM DTT and heating at60° C. for 3 min. The mass of the Fd (Vh-CH1) and LC fragments wereanalyzed by ESI-MS. 7G6-HCzu8 contained an N-terminal pyroglutamic acid,a typical post-translational modification of N-terminal glutamines. Allobserved masses were within 3 Daltons of the predicted masses (Table 9).

TABLE 9 ESI-MS analysis of humanized variants Fd PyrQ Cys CalculatedObserved dMass 7G6- 25447 17 4 25426 25425 −1 HCzu8- LCzu6 7G6- 25447 174 25426 25425 −1 HCzu8- LCzu21 7G6- 25349 4 25345 25345 0 HCzu23- LCzu157G6- 25526 4 25522 25522 0 HCzu24- LCzu15 7G6- 25469 4 25465 25463 −2HCzu25- LCzu15 7G6- 25349 4 25345 25345 0 HCzu23- LCzu18 7G6- 25526 425522 25521 −1 HCzu24- LCzu18 7G6- 25469 4 25465 25462 −3 HCzu25- LCzu18LC Cys Calculated Observed dMass 7G6- 24007 4 24003 24003 0 HCzu8- LCzu67G6- 23991 4 23987 23988 1 HCzu8- LCzu21 7G6- 23953 4 23949 23949 0HCzu23- LCzu15 7G6- 23953 4 23949 23949 0 HCzu24- LCzu15 7G6- 23953 423949 23948 −1 HCzu25- LCzu15 7G6- 23967 4 23963 23963 0 HCzu23- LCzu187G6- 23967 4 23963 23963 0 HCzu24- LCzu18

10B.c.2 Tau Binding BIAcore™ Assay

Tau binding for humanized mAbs was analyzed by BIAcore™ in two differentformats. The first format was performed as above, i.e. mAbs werecaptured with an immobilized species-specific anti-Fc antibody. Thelimitation of this format is seen in Tables 5 and 8 where the affinitiesof the parental mouse and humanized mAbs cannot be directly compared dueto the differences in the capture antibodies. In the second format,biotinylated mAbs were captured on a streptavidin-coated chip. Thislatter format allowed direct comparison of Tau binding affinity betweenhumanized and the parental mouse antibody since the capture method wasidentical.

10B.c.2.i Fc-Specific Capture

The final humanized mAbs were analyzed by BIAcore™ to determine thek_(a), k_(d), and K_(D) for binding to Tau as above (Table 10). Therewas a significant change in the off rate (10 from 7G6-HCzu23 to7G6-HCzu24, while 7G6-HCzu24 was similar to 7G6-HCzu25, which was alsoseen in the overall affinity K_(D) as well. This confirmed theimportance of retaining mouse residues in CDRH2, as seen above in Table7.

TABLE 10 BIAcore ™ analysis of humanized 7G6 mAbs binding monomeric Tau(anti-human capture) k_(a) (×10⁵ k_(d) (×10⁻³ K_(D) MAb M⁻¹sec⁻¹) sec⁻¹)(nM) 7G6-HCzu8-LCzu6 14.9 0.22 0.15 7G6-HCzu23-LCzu15 16.1 0.39 0.257G6-HCzu24-LCzu15 8.09 0.11 0.13 7G6-HCzu25-LCzu15 9.85 0.13 0.137G6-HCzu23-LCzu18 17.1 0.37 0.22 7G6-HCzu24-LCzu18 9.48 0.09 0.097G6-HCzu25-LCzu18 11.1 0.14 0.13

Streptavidin Capture

Biotinylated humanized and mouse mAbs were captured on astreptavidin-coated chip and k_(a), k_(d), and K_(D) were determined forbinding to Tau (Table 11). 7G6-HCzu8-LCzu21 showed a slight drop inaffinity (<2-fold) compared with 7G6-HCzu8-LCzu6. Similarly, 7G6-HCzu23variants had an ˜2-fold drop in affinity compared to 7G6-HCzu24 and7G6-HCzu25 mAbs, as seen in Table 11. The affinity of 7G6-HCzu8-LCzu6,7G6-HCzu24-LCzu15, 7G6-HCzu24-LCzu18, 7G6-HCzu25-LCzu15, and7G6-HCzu25-LCzu18 were all similar. Overall, these antibodies showed an˜1.4-fold drop in affinity compared with the ms7G6, reflected mainly ina slightly faster off-rate for the humanized forms.

TABLE 11 BIAcore ™ analysis of humanized 7G6 mAbs and mouse 7G6 bindingmonomeric Tau (streptavidin capture) k_(a) (×10⁵ k_(d) (×10⁻³ K_(D) MAbM⁻¹sec⁻¹) sec⁻¹) (nM) 7G6-HCzu8-LCzu6 28.20 0.258 0.09157G6-HCzu8-LCzu21 22.80 0.313 0.1380 7G6-HCzu23-LCzu15 21.80 0.332 0.15207G6-HCzu23-LCzu18 21.40 0.390 0.1820 7G6-HCzu24-LCzu15 54.20 0.4870.0898 7G6-HCzu24-LCzu18 38.10 0.304 0.0797 7G6-HCzu25-LCzu15 27.100.270 0.0998 7G6-HCzu25-LCzu18 35.00 0.307 0.0881 ms7G6 31.10 0.1950.0636

10B.c.3 Analysis of Homogeneity and Aggregation by SEC-HPLC

Each mAb was analyzed by SEC-HPLC to determine the homogeneity of themAb in solution. The profiles of 7G6-HCzu8-LCzu6 and 7G6-HCzu8-LCzu21mAbs were identical, with a main peak at 14.5 min and wide shouldersuggesting possible product heterogeneity beyond 16 minutes (FIG. 21A).The profiles of 7G6-HCzu23, 7G6-HCzu24, and 7G6-HCzu25 mAbs wereidentical, with a tight peak around 14.7 min (FIG. 21B).

10B.c.4 DSC Analysis

The thermal melting curves of F(ab′)2 fragments were analyzed bydifferential scanning calorimetry (DSC). The profiles of the chimeric,7G6-HCzu8 and 7G6-HCzu25 F(ab′)2 were similar to control non-Tau bindinghuman IgG1 antibodies, mAb1 and mAb2. 7G6-HCzu23 and 7G6-HCzu24,however, contained a second peak, indicating instability of the F(ab′)2fragment, possibly the dissociation of the HC-LC interaction (FIGS.22A-L). The transition midpoints of 7G6-HCzu8-LCzu21, 7G6-HCzu25-LCzu15,and 7G6-HCzu25-LCzu18 were similar, ranging from 77.4 to 77.6° C. Themidpoint of 7G6-HCzu8-LCzu6 was one degree higher at 78.6° C. (Table12).

TABLE 12 Melting transition midpoints of humanized 7G6 F(ab′)2 fragmentsTransition Transition Analysis 1 Midpoint-1 Midpoint-2 7G6-HCzu8-LCzu6N/A 78.61 7G6-HCzu23-LCzu15 67.81 73.41 7G6-HCzu24-LCzu15 68.04 73.387G6-HCzu25-LCzu15 N/A 77.42 7G6-HCzu23-LCzu18 67.81 73.417G6-HCzu24-LCzu18 68.78 73.26 7G6-HCzu25-LCzu18 N/A 77.6  TransitionTransition Analysis 2 Midpoint-1 Midpoint-2 7G6-HCzu8-LCzu6 N/A 78.587G6-HCzu8-LCzu21 N/A 77.51

10B.d T Cell Epitope Analysis

Humanized sequences were analyzed in silico by Stealth Biologics forpotential immunoreactive T cell epitopes. Two sequences for eachvariable region germline family were analyzed, each contained differingamounts of human and mouse residues. mAb1-2a and mAb1-2b representedIGHV1-46a/IGKV2-30a and mAb3-1a and mAb3-1b representedIGHV3-23b/IGKV1-39b. Though only four sequences were analyzed for eachvariable domain, all potential T cell epitopes present in the testedhumanized mAbs were represented. Peptide epitopes having identity togreater than 5% of human germline sequences were considered lower risk,as were peptides binding only one or two HLA alleles.

FIGS. 23 and 24 summarize the analysis of epitopes present in the mAbs.The peptides in the tables were identified as having 5% or less identityto human germline sequences. The percent homology of the peptides tovariable domain germline sequences was also taken into consideration.Peptides with ˜5% or less homology to variable region germline sequencesand/or were predicted to bind three or more HLA alleles were identifiedas higher risk (highlighted in gray).

7G6-HCzu8 and 7G6-HCzu25 both contained a common low-risk peptide atposition 32 with no homology to germline sequences that bound 3 alleles(FIGS. 23A and 23B). Peptide 2 was predicted to be a low risk in7G6-HCzu25, but the 7G6-HCzu8 peptide 2 was not. Peptide 64 was presentas a risk in both HCs, predictively binding 3 alleles. The peptidesequence in 7G6-HCzu8 may present less of a risk as it has some homologyto germline variable domains. Peptide 70 in 7G6-HCzu8, but not7G6-HCzu25, posed a slight risk.

There was one difference between 7G6-LCzu6 and 7G6-LCzu21 where peptide38 in 7G6-LCzu21 was predicted to bind 1 HLA allele but presented a verylow risk (FIGS. 24A-24D). Between 7G6-LCzu15 and 7G6-LCzu18 there wasonly one difference with peptide 2 that posed a higher risk in7G6-LCzu15 than 7G6-LCzu18 as there was little to no homology tovariable domain germline sequences. Comparing 7G6-LCzu6/7G6-LCzu21 with7G6-LCzu15/7G6-LCzu18, 7G6-LCzu6/7G6-LCzu21 sequences contained 9potentially immunogenic peptides while 7G6-LCzu15/7G6-LCzu18 contained6. Peptides 51 and 52 were the same between all LCs and peptides 88-94were the same or similar, with the exception being peptide 90 present in7G6-LCzu6/7G6-LCzu21 that was not present in 7G6-LCzu15/7G6-LCzu18.Peptides 2 and 3 were riskier in 7G6-LCzu6/7G6-LCzu21 than in7G6-LCzu15/7G6-LCzu18.

10C. Summary

In summary, ms7G6 was humanized on two different human germline variabledomain families with similar affinity to ms7G6.

The human germlines closest to the mouse sequence were IGHV1-46 andIGKV2-30. Even though several mouse framework residues were suspected tobe required to maintain antigen binding, Tau binding was not affected byhuman framework residue (7G6-HCzu1/7G6-HCzu8). Further, Tau binding wasnot affected by mutation of the unpaired Cys57 to a serine(7G6-HCzu5/7G6-HCzu8) or super-humanization of CDRH2 at residues 60, 61,64, and 65 (7G6-HCzu4/7G6-HCzu8). Grafting the Vκ CDRs on the IGKV2 didnot result in a dramatic decrease in Tau binding, but the addition ofone or two mouse framework residues stabilized the HC-LC interaction.Leu46 with or without Tyr36 increased the stability of Vh-Vκinteraction, as analyzed by SDS-PAGE, and the Tyr36-Leu46(7G6-LCzu2/7G6-LCzu6) combination resulted in an antibody with slightlyhigher affinity to Tau than with Leu46 or Tyr36 alone(7G6-LCzu/7G6-LCzu21 and 7G6-LCzu4/7G6-LCzu22, respectively). Thoughthere was a slight risk in immunogenicity with a leucine at position 46,the risk was low. The unpaired Cys49 could be substituted with a serine,but a tyrosine substitution resulted in an increase in the dissociationrate.

The human germline variable domain families IGHV3-23 and IGKV1-39 werechosen to potentially reduce the immunogenicity of the humanized mAb byutilizing the more commonly expressed IGHV3 and IGKV1 families. GraftingCDRs onto the IGHV3 germline required one or more mouse residues. Arg94could not be the human lysine residue. Mouse residues at positions 60,61, 62, 63, and 65 were required for optimal antigen binding. Anarginine at 71 did not affect antigen binding but was required forstability of the Vh-Vκ interaction (7G6-HCzu12, 7G6-HCzu13, 7G6-HCzu14,7G6-HCzu15, 7G6-HCzu16, 7G6-HCzu17, 7G6-HCzu25). Although Va171 resultedin a potentially immunogenic peptide when paired with Phe63 and Ser65,the risk was low. Tau binding was not affected by mutation of theunpaired Cys57 to a serine (7G6-HCzu23, 7G6-HCzu24, 7G6-HCzu25). Humanresidues throughout the IGKV1 framework did not affect antigen bindingor stability (7G6-LCzu18).

For all antibodies tested, there were little differences in the pI andthermal stability.

Example 11: Immunohistochemistry with 7G6-HCzu25/LCzu18 on Human DiseaseBrain

Paraffin-embedded, fixed human brain sections (8 μm) were dewaxed withmultiple changes of xylene and then washed thoroughly in 100% IndustrialMethylated Spirit (IMS). Sections were placed into hydrogen peroxide(H₂O₂) and methanol (2 mL hydrogen peroxide per 100 mL methanol) for 10minutes at room temperature to block endogenous peroxidase and thenwashed under running tap water for a further 10 minutes. Each sectionwas then treated with 98% formic acid for 10 minutes at room temperaturefollowed by washing in running tap water for another 10 minutes.Sections were then cooked in citrate buffer (pH 6.0) for 10 minutes atpressure and then washed again in running tap water followed by TBS.After a rinse in de-ionized water, each slide was carefully removed anddried around the tissue edge. Once dry, a wax pen was used to markaround the section before applying a Proteinase K solution for 10minutes at room temperature.

Once tissue sections were prepared, staining with the 7G6-HCzu25-LCzu18antibody at different concentrations was carried out with the KlearHuman HRP-Polymer DAB Detection Kit (GBI Labs, Bothwell, WA; Cat No.D103-18) as per the manufacturer's instructions. As shown in FIG. 25 ,antibody 7G6-HCzu25-LCzu18 strongly and specifically recognizespathological Tau in brains from Alzheimer's disease (neurofibrillarytangles and neuropil threads), PSP (tangles, tufted astrocytes andcoiled bodies) and Pick's disease (Pick bodies) by immunohistochemistry.The antibody also showed only a very low level of background staining inall tissues tested.

Example 12: Affinity of 7G6-HCzu25-LCzu18 to 2N4R Wild Type Tau 12A.Materials & Methods

12A.c.2. CHO Transient mAb Production

7G6-HCzu25-LCzu18 antibody was produced using the Lonza version 7platform according to the manufacturer's procedures. DNA fragmentsencoding 7G6-HCzu25 and 7G6-LCzu18 were cloned into an expressionplasmid encoding glutamine synthase from Lonza. According to Lonza'sprotocol for selecting MSX-resistant cell lines, CHO-K1sv cells wereelectroporated with the 7G6-HCzu25-LCzu18 expression plasmid, followedby seeding 2500 cells per well in 96-well plates in glutamine-freemedium in the presence of 25 or 5011M MSX. Wells containingMSX-resistant cell were subjected to several rounds of screening forantibody expression at various cell culture volumes. The cell line 96E7producing the highest 7G6-HCzu25-LCzu18 antibody titers was chosen forfurther development and frozen at −80° C. and stored in vapor phase inliquid nitrogen.

A vial of cell line 96E7 was thawed and cultivated in disposable shakeflasks at 36.5° C. and 5% CO₂ followed by further expansion every 3-4days in larger-sized disposable rocking bags at 36.5° C. and 5% CO₂. A200 L stainless steel seed bioreactor was employed to final expansion at36.5° C. with controlled pH and dissolved oxygen prior to theinoculation of a 1000 L stainless steel fed-batch production bioreactor.After 15 days at fed-batch mode and 36.5° C. with controlled pH anddissolved oxygen, the supernatant was harvested through depthfiltration.

12A.d. MAb Purification

Purification was performed using an AKTA process purification platform(GE Healthcare). The purification process consisted of the followingsteps: Protein A capture chromatography, viral inactivation, depthfiltration, anion-exchange flow through chromatography, viral reductionfiltration, concentration and final buffer exchange.

The primary capture step was performed using Amsphere A3 Protein A resin(JSR). The 14.1 L column was equilibrated using 50 mM sodium phosphate,1 M NaCl, pH 7.0 then loaded up to 45 g protein per liter of resin percycle. After loading, the column was washed with equilibration bufferfollowed by 25 mM Bis-Tris, pH 7.0 until UV returned to baseline. Boundmaterial was eluted from the column using 100 mM Glycine, pH 3.4. The pHof the eluate was adjusted to pH 3.6 using 2 M Acetic Acid for low pHviral inactivation. Following a minimum 30 minute static hold, theeluate was neutralized to pH 6.8 using 2 M Tris Base. Depth filtrationwas immediately performed using Millistak+DOHC and X0HC pod filters(Millipore). The filtrate was further processed using a 6.7 L Capto Q(GE Healthcare) anion exchange column equilibrated in 25 mM Bis-Tris, pH7.0. The column was loaded up to 150 g protein per liter of resin innon-binding mode. The flow-through product was filtered using aViresolve Pro viral reduction filter then concentrated to 25 g/L. Thematerial was buffer exchanged into a buffer. The purification procedurewas performed on two different monoclonal antibody production runs anddesignated lots 17-0190 and 18-0146. Several vials from lot 17-0190 weredesignated 17-0190ARS for use as a reference standard.

12A.f. Surface Plasmon Resonance (SPR) Binding Analyses

12A.f.2. Anti-Human Capture Monomeric Tau-Binding Assay

12A.f.2.i. Chip Preparation

Reagent preparation. EDC [1-ethyl-3(3-dimethylaminopropyl)carbodiimide]and NHS (N-hydroxysuccinimide) were dissolved by adding 10.0 ml ofMilli-Q water to each vial. Vials were capped tightly and vortexed untilthe solids were completely dissolved. EDC, NHS, and ethanolaminesolutions were aliquoted separately into 0.5 ml aliquots in 7 mm plasticvials, capped, and stored frozen at −20° C. Anti-human IgG (Fc) from kitwas centrifuged in microfuge briefly to collect antibody at bottom oftube. 15 μL anti-human IgG (Fc) was removed to a new 1.5 mL microfugetube and diluted to 300 μL with 285 μL immobilization buffer. Sample wasvortexed briefly to mix, then 70 μL was aliquoted to 4 separate 7 mmtubes and capped. 4 aliquots each of EDC, NHS, and ethanolamine werethawed, vortexed briefly to mix and displace any air bubbles trapped ontube walls, and placed in Reagent Rack 2.

0.5 L of 1×HBS-P+(Assay Running Buffer) was prepared by diluting 50 mLHBS-P+ to 0.5 L with 450 mL Milli-Q® water in 1 L Pyrex bottle.

Preparation of instrument for assay. A 1 L bottle of Assay RunningBuffer was attached to Buffer A line on BIAcore® T-100, an empty 2 LPyrex bottle to BIAcore® T-100 waste line, and a 1 L Pyrex bottle filledwith fresh 1 L Milli-Q® water to water line. A new CMS chip was dockedinto the instrument.

Capture antibody immobilization. In BIAcore® T-100 Control software, anew Wizard Template was opened and “Immobilization” was selected. Chiptype was set to “CMS”. Method was set to “Amine”. Ligand blanks werefilled in as “anti-human”. Contact time was set to 360 sec for each flowcell and flow rate 5 μL/min. Following completion of these steps, assaywas run.

12A.f.2.ii. Binding Assay

Binding experiments were performed using a BIAcore™ T-100 instrument ora T-200 instrument. Running buffer used for the binding assay wasHBS-P+/0.2% BSA. 7G6-HCzu25LCzu18 samples were diluted to 100 μg/mL, 100μL final in Assay Running Buffer, then centrifuged at 18,000×g for 10min in microcentrifuge at ambient temperature. Dilution to 1 μg/mL wasdone by removing 40 μL supernatant and diluting to 4.0 mL with AssayRunning Buffer in labeled 5 mL tubes. 1 μg/mL antibody solutions weretransferred to labeled 1.5 mL capless plastic vials and capped with type3 caps. Vials were vortexed briefly to remove any air bubbles adhered totube walls or bottom and placed in Sample and Reagent Rack 1. 200 μL 1μg/mL solution of diluted reference standard antibody was transferred toa 7 mm plastic vial, capped, vortexed briefly to dislodge adhered airbubbles, and placed in Sample and Reagent Rack 1 (for chip conditioningcycles). Recombinant human wild-type 2N4R tau protein was diluted to 1μM, 0.5 mL final in Assay Running Buffer (1 mg/mL stock is 21.7 μM).Sample was centrifuged at 18,000×g for 10 min in microcentrifuge atambient temperature and diluted to 100 nM by removing 400 μL supernatantand diluting to 4.0 mL with Assay Running Buffer in a labeled 5 mL tube.100 nM solution was serially diluted 3-fold by removing 1333 μL 100 nMsolution and diluting in 2667 μL Assay Running Buffer to a final volumeof 4.0 mL (33.3 μL). Serial dilution was repeated 6 times, for a totalof 8 dilutions (100 nM, 33.3 nM, 11.1 nM, 3.70 nM, 1.23 nM, 0.41 nM,0.14 nM, and 0.046 nM tau). A 0 nM Tau protein solution was prepared byadding 3 mL Assay Running Buffer to labeled 5 mL tube. Analyte dilutionswere transferred to labeled 4 mL plastic vials and capped with type 5caps, vortexed briefly to remove any air bubbles adhered to tube wallsor bottom, and placed in Sample and Reagent Rack 1. For chipconditioning analyte sample, 5 μL of 1 μM Tau protein solutionsupernatant was removed and diluted to 500 μL in Assay Buffer in a 7 mmplastic vial, capped, vortexed briefly to dislodge adhered air bubbles,and placed in Sample and Reagent Rack 1. Humanized antibodies werecaptured on flow cells 2, 3, and 4 sequentially at a flow rate of 10μL/min for a contact time of 36 sec. Dilutions of Tau protein wereinjected over all 4 flow cells at a flow rate of 30 μL/min for a contacttime of 300 sec. Dissociation was followed for 1800 sec. Following eachcycle, the surface was regenerated by two sequential injections of 30sec at 30 μL/min of 3 M MgCl₂ over all four flow cells. After the run,kinetic data fitting was performed using a 1:1 Langmuir model.

12B. Results

The affinity of recombinant human wild-type 2N4R Tau protein to7G6-HCzu25LCzu18 antibody was determined using an antibody-captureformat assay. Following capture of 7G6-HCzu25LCzu18 antibody, human Tauprotein was injected over the ligand surface for 300 sec, followed byobservation and measurement of dissociation for 1800 sec. After eachantibody capture, Tau protein binding, and dissociation cycle, the chipsurface was regenerated to the anti-human antibody capture surface using3M MgCl₂, as required by the manufacturer. Tau protein was analyzed in aconcentration range from 100 nM to 0.046 nM (3-fold diluted). The assaywas performed in multi-cycle mode, such that a dissociation wasperformed for each tau protein injection. Each ligand was analyzed onall three flow cells (fc2, fc3, and fc4) in triplicate, in order toeliminate any flow cell-specific effects.

Capture levels of each ligand on each flow cell (relative to fc1) weredetermined. These results are listed in Table 13:

TABLE 13 Capture levels of 7G6-HCzu25-LCzu18 ligands fc2 fc3 fc47G6-HCzu25LCzu18, 189.9 185.6 196.1 lot 17-0190 7G6-HCzu25LCzu18, 177.0173.7 183.1 lot 18-0146 7G6-HCzu25LCzu18, 161.7 158.1 166.7 lot17-0190ARS Data are expressed in RU. Values represent averages of ligandcapture levels for all relevant cycles. fc - flow cell

Captured ligand average levels were all between 158 RU and 196 RU. Onlyslight differences were observed between flow cells within a givenligand.

Binding data was double-referenced, meaning referenced to both fc1 withno ligand bound and to buffer analyte injections (0 nM Tau protein).Binding data was fitted to a 1:1 Langmuir binding model. This model isappropriate for the assay format, as bivalency of the antibody andresulting avidity effects are not relevant in an antibody captureformat. Affinity data for each ligand on individual flow cells wasaveraged and standard deviation determined. These results are listed inTable 14:

TABLE 14 Affinity constants for human Tau binding to 7G6-HCzu25LCzu18k_(a) (M⁻¹sec⁻¹) k_(a) (sec⁻¹) K_(D) (M) 7G6-HCzu25LCzu18, 1.919 ± 0.108× 10⁶ 1.256 ± 0.022 × 10⁻⁴ 6.565 ± 0.493 × 10⁻¹¹ lot 17-01907G6-HCzu25LCzu18, 1.916 ± 0.093 × 10⁶ 1.259 ± 0.027 × 10⁻⁴ 6.587 ± 0.460× 10⁻¹¹ lot 18-0146 7G6-HCzu25LCzu18, 1.914 ± 0.027 × 10⁶ 1.235 ± 0.018× 10⁻⁴ 6.451 ± 0.163 × 10⁻¹¹ lot 17-1090ARS

No significant differences in on rate, off-rate, or affinity wereobserved between the two 7G6-HCzu25LCzu18 drug substance lots and7G6-HCzu25LCzu18 reference standard.

Example 13: Fine Epitope Mapping of 7G6-HCzu8-LCzu6 and7G6-HCzu25-LCzu18

Fine epitope mapping was performed for 7G6-HCzu8-LCzu6 and7G6-HCzu25-LCzu18 antibodies as described in Example 3.

The fluorescent images of the chips and resulting intensity plots showthat the 7G6-HCzu8-LCzu6 (FIG. 26A) and 7G6-HCzu25/LCzu18 (FIG. 26B)antibodies both bind to two major sites on the full length Tau protein,similar to the murine 7G6 antibody (see FIG. 3 ). A strongerfluorescence intensity on the chip was observed generally for7G6-HCzu25-LCzu18 resulting in some signs of signal saturation andtherefore lack of true quantification for some but not all of thepeptides. In this experiment, the data analysis software (PepSlide™Analyser) identified the minimum binding sequence for 7G6-HCzu8-LCzu6 asKHVPGGG (SEQ ID NO: 1135) for the site within the second repeat(positions 298 to 304) and HVPGG (SEQ ID NO: 79) for the site within thefourth repeat (positions 362 to 366) of 2N4R protein. For7G6-HCzu25-LCzu18, the software identified the minimum required sequenceas HVPG (SEQ ID NO: 1133) for both binding sites.

Similar to murine 7G6, minor binding was observed at two additionalsites: HQPGG (SEQ ID NO: 183) at amino acid positions 268 to 272 andHKPGG (SEQ ID NO: 182) at positions 330 to 334 for both 7G6-HCzu8-LCzu6and 7G6-HCzu25-LCzu18 antibodies. Calculation of average signalintensities for peptides containing the HXPGG sequence (SEQ ID NO: 1136)demonstrated that the 7G6-HCzu8-LCzu6 human antibody showed a 108-foldor 104-fold preference in binding to the HVPGG site (SEQ ID NO: 79)normally contained within the second repeat region of full length 2N4RTau compared to the HQPGG (SEQ ID NO: 183) (repeat region 1) or HKPGG(SEQ ID NO: 182) (repeat region 3) sequences, respectively. Similarly, a99-fold or 95-fold preference in 7G6-HCzu8-LCzu6 binding to the HVPGG(SEQ ID NO: 79) site normally contained within the fourth repeat regionof full length 2N4R Tau compared to the HQPGG (SEQ ID NO: 183) (repeatregion 1) or HKPGG (SEQ ID NO: 182) (repeat region 3) sequences,respectively, was observed. Identical data analysis for7G6-HCzu25-LCzu18 demonstrated a 65-fold or 100-fold preference inbinding to the HVPGG (SEQ ID NO: 79) site normally contained within thesecond repeat region of full length 4R Tau compared to the HQPGG (SEQ IDNO: 183) (repeat region 1) or HKPGG (SEQ ID NO: 182) (repeat region 3)sequences, respectively. Likewise, a 77-fold or 119-fold preference in7G6-HCzu25-LCzu18 binding to the HVPGG (SEQ ID NO: 79) site normallycontained within the fourth repeat region of full length 4R Tau comparedto the HQPGG (SEQ ID NO: 183) (repeat region 1) or HKPGG (SEQ ID NO:182) (repeat region 3) sequences, respectively, was observed.

Example 14: Epitope Substitution Scanning of 7G6-HCzu8-LCzu6 and7G6-HCzu25-LCzu18

Epitope substitution scanning was performed for 7G6-HCzu8-LCzu6 and7G6-HCzu25-LCzu18 antibodies as described in Example 4.

The substitution scanning showed that of the ¹HVPGG⁵ (SEQ ID NO: 79)sequence, both 7G6-HCzu8-LCzu6 and 7G6-HCzu25-LCzu18 antibodies requirethe ¹H, ³P and ⁴G residues with some substitution tolerability at ²V forpeptide binding. These findings were similar to those observed for themurine 7G6 antibody (see Example 4). Some tolerability for substitutionwas also observed at the second glycine residue (⁵G) of the ¹HVPGG⁵ (SEQID NO: 79) sequence in this case. However, this residue was still ableto exert considerable influence over the binding of 7G6-HCzu25-LCzu18and 7G6-HCzu8-LCzu6 antibodies to the longer wild type peptide sequence.Together with Example 13, these results indicate that the HVPGG (SEQ IDNO: 79) sequence facilitates efficient binding of 7G6, 7G6-HCzu25-LCzu18and 7G6-HCzu8-LCzu6 antibodies to 2N4R Tau at positions 299 to 303 and362 to 366 within the second and fourth repeats, respectively.

Example 15: In Vitro Tau Aggregation with 7G6-HCzu25-LCzu18 Experiment 1

To determine whether 7G6-HCzu25-LCzu18 antibody could inhibit Tauaggregation in vitro, the antibody was tested in the assay described inExample 5 using the wild type Tau protein with minor modifications. Theonly difference was the control IgG used in this case was a human IgG1antibody (BioXCell, catalogue number BE0297).

In this assay, 7G6-HCzu25-LCzu18 antibody was tested over a time courseof several days. FIG. 27 shows that 7G6-HCzu25-LCzu18 could effectivelyinhibit Tau aggregation in vitro. The effect was statisticallysignificant (t-test) when comparing the IgG control and7G6-HCzu25-LCzu18 for days 1, 2, 5 and 6 following incubation at 37° C.No significance was observed on day 0 just after the reactions wereinitiated following heparin addition.

Experiment 2

To confirm the humanized 7G6-HCzu25-LCzu18 antibody was comparable tothe murine 7G6 antibody at inhibiting Tau aggregation in vitro, bothantibodies were compared in the same in vitro Tau aggregation assay. Theconditions used were identical to those in Experiment 1 of this Examplewith the exception that the same mouse IgG2b control antibody was usedthat was described in Example 5.

When both murine antibody 7G6 and humanized antibody 7G6-HCzu25-LCzu18were tested according to the assay conditions provided in Example 5,both antibodies effectively inhibited Tau aggregation in vitro. As shownin FIG. 28 , the same effect size was seen between murine 7G6 and7G6-HCzu25-LCzu18 antibodies.

Example 16: Cell-Based Seeding Assay Using K18 Tau Fibril FollowingImmunodepletion with 7G6-HCzu25-LCzu18

To determine whether immunodepletion of Tau seeds from cell culturemedium could prevent further Tau aggregation within cells, the sameHEK293 assay system as described in Example 6 was used. In this casehowever, a potent truncated form of Tau (K18) fibrils were used as Tauseeds rather than full length protein as described previously. The K18fragment has been studied extensively and is normally expressedrecombinantly as residues 244 to 372 of the full length 2N4R Tauprotein. This fragment encodes the microtubule binding region of Tau andhas been reported to be more aggregate-prone than the full lengthprotein (Shammas et al., Nature Comms., 6, Article number: 7025 (2015))as well as having the ability to form potent seeds in cell-based assays(Kfoury et al., 2012, J. Biol. Chem., 287: 19440-19451).

Materials and Methods:

Preparation of K18 fibrils. Recombinant human Tau-441 (244-372; “K18”)(SignalChem) was dissolved in ultrapure water. Fibrils were generated bymixing together final concentrations of 40 μmol/L K18 protein, 100mmol/L sodium acetate (pH 7), 2 mmol/L DTT and 240 μg/mL heparin.Reactions were agitated for three days at 37° C. Following incubation,the solution was centrifuged at 135,000 g for 20 minutes at roomtemperature. The supernatant was discarded, and the pellet wasresuspended in 100 mmol/L sodium acetate (pH 7). Aggregated protein wassonicated briefly and then diluted with D-PBS (−) to a concentration ofμg/mL and stored at −80° C.

Preparation of immunodepleted and immunoprecipitated samples.Immunoprecipitation of the prepared K18 fibrils was performed using theImmunoprecipitation Dynabeads® Protein G kit (Thermofisher Scientific,catalogue number 10007D) as per the manufacturer's instructions.Briefly, each immunoprecipitation used 1.5 mg of Dynabeads bound toeither 3 or 0.3 μg of 7G6-HCzu25-LCzu18 antibody. Vehicle (no antibody)or 3 μg of commercially available human IgG1 antibody (Bio-RadLaboratories, Inc.; catalog number HCA192) were included as controls.Antibody-bound (or vehicle-treated) beads were resuspended in 170 μL ofbuffer containing 0.2% BSA. The K18 fibril solution was then thawed,diluted to 10 μg/mL in PBS, and added to the antibody-bound beads togive a final volume of 200 μL (containing 300 ng of K18 total). Thisgave final concentrations of either 15 or 1.5 μg/mL of antibody in eachimmunoprecipitation reaction. Beads were incubated with the K18 fibrilsfor 20 minutes at room temperature with rotation and non-bound materialwas retained as the immunodepleted (ID) sample. Antibody-bound materialwas eluted in 20 μL of the buffer provided in the kit and also retainedto provide the immunoprecipitated (IP) samples.

Cell-based assay. Polyethylenimine (PEI) solution was diluted inpurified water to a final concentration of 0.1% and then used to coat a96-well tissue culture plate at 37° C. for at least one night. Plateswere then washed twice with water before adding 150 μl of Dulbecco'smodified Eagle's Medium (D-MEM) containing 10% fetal bovine serum and 1%penicillin/Streptomycin (“DMEM (+FBS, P/S)”) medium to each well priorto conducting the assay.

Lenti-X 293T (Takar Bio Inc.) cells routinely maintained in D-MEM (+FBS,P/S) at 37° C. with 5% CO₂ were transfected in suspension in the samemedia without antibiotics prior to Tau seed addition. For transfection,7 μg of pcDNA3.1(+) (Invitrogen) mammalian expression vector containingcDNA encoding the mutant P301S 0N4R Tau isoform was mixed with LTX andPlus™ Reagent (Life Technologies, catalog number 15228-100) as per themanufacturer's recommendation. The resulting mixture was incubated forat least 25 minutes at room temperature before adding directly to asuspension of 6.0×10⁶ Lenti-X 293T cells at a density of 1.0×10⁵cells/mL. Media was removed from the precoated plate and the treatedcell suspension was dispensed at 150 μL per well (1.5×10⁴ cells/well)and incubated for 19 hours at 37° C. in a 5% CO₂ atmosphere.

Once thawed on ice, 30 lit of each ID sample was diluted into 420 μL ofOpti-MEM® I Reduced-Serum Medium (ThermoFisher Scientific, catalognumber 31985-062). For IP samples, solutions were also thawed on ice and2 μL of each was diluted into 50 lit of Opti-MEM® I Reduced-SerumMedium. Then 2.5 μL of P3000 (Thermofisher Scientific, catalog numberL3000-008) was added. In a separate tube, 22 μL of Lipofectamine® 3000(Thermofisher Scientific, catalog number L3000-008) was diluted into 550μL Opti-MEM® I Reduced-Serum Medium. Then, 52 μL of the dilutedLipofectamine 3000 solution was added to each IP sample containing theP3000 reagent.

Plated cells were washed twice and left in 75 μL of Opti-MEM® IReduced-Serum Medium (ThermoFisher Scientific). An equal volume ofdiluted ID or IP sample as described above was added to each well andincubated for 44 hours at 37° C. in a 5% CO₂ atmosphere. The experimentwas performed in quadruplicate.

Immunocytochemistry. After two days of incubation, cells were fixed in4% paraformaldehyde for 30 minutes at room temperature. Each well waswashed 3 times with 100 lit of purified water and then left in 70 μL ofPermeabilization/Blocking/DAPI staining buffer (Triton X-100 solution(final concentration: 0.2%) and Cellstain® DAPI solution (finalconcentration: 0.1%; Dojindo) diluted in 5% BSA in TBS) was added toeach well. The plate was covered and incubated for 30 minutes at roomtemperature with protection from light. After incubation,Permeabilization/Blocking/DAPI staining buffer was removed, and 804Thioflavin S (ThS) staining buffer (Thioflavin S dissolved in 50%Ethanol to a final concentration of was added to each well and incubatedfor 40 minutes at room temperature. Then, each well was washed twicewith 50% ethanol and replaced with 250 μL of purified water.

Imaging assay. Fluorescence images of each well were obtained by anInCell® Analyzer 2200 (GE Healthcare) (ThS: Excitation [Ex]/Emission[Em]=475/511 nm, DAPI: Ex/Em=390/435 nm). Numbers of ThS and DAPIpositive signal in each well were then analyzed using the InCellDeveloper Software (GE Healthcare).

Data Analysis. The ThS positive rate was calculated using the followingformula:

$\begin{matrix}{{{ThS}{positive}{rate}} =} & {{ThS}/{DAPI}} \\ = & {{number}{of}{ThS}{positive}{signals}/} \\\text{} & {{number}{of}{DAPI}{positive}{{signals}.}}\end{matrix}$

Then, the seeding effect of ID or IP samples were calculated using thefollowing formulas (Software: TIBCO Spotfire):

-   -   The seeding effect of ID sample (% of control)=T₁/C₁×100, where    -   T₁: Average of ThS positive rate in the antibody treated ID        sample, and    -   C₁: Average of ThS positive rate in the buffer treated ID        sample.    -   The seeding effect of IP sample (% of control)=T₂/C₂×100, where    -   T₂: Average of ThS positive rate in the antibody treated IP        sample, and    -   C₂: Average of ThS positive rate in the 7G6-HCzu25-LCzu18        antibody (15 μg/mL)-treated IP sample.

FIG. 29 shows the normalized ThS positive rate in the cell-based seedingassay after treatment of ID samples. 1.5 and 15 μg/ml of7G6-HCzu25-LCzu18 antibody removed the seeding effects of K18 fibril(>70% reduction vs human IgG1 kappa control). For the IP samples,7G6-HCzu25-LCzu18 antibody efficiently induced seeding effects in aconcentration-dependent manner (data not shown).

Example 17: Intrahippocampal P301S Tau Seed Injection Model with 7G6Materials and Methods:

Tau seed was generated by mixing recombinant human 2N4R P301S Tau (40μmol/L) and heparin (240 μg/mL), followed by an incubation step at 37°C. for 48 to 96 hours in 100 mmol/L sodium acetate, pH7.0, containing 2mmol/L Dithiothreitol (DTT). Aggregated Tau was collected byultracentrifugation and resuspended in 100 mmol/L sodium acetate, pH7.0.The resulting fibrils were sonicated and used as seeds for injection.

3 μL of Tau seed (1.5 mg/mL) or non-seed (100 mmol/L sodium acetate,pH7.0) was stereotaxically injected into left hippocampus (A: +2.5, L:2.0, V: 1.5) (Franklin and Paxinos, The Mouse Brain in StereotaxicCoordinates Third Edition 2007, Elsevier USA) of 3-to 4-month-oldMouse/Thy-1hTau.P301S (CBA.C57BL/6) mice [homozygous human P301S Tautransgenic mouse (C57BL/6) generated previously (Allen et al., JNeurosci. 2002; 22:9340-51)] using an UltraMicroPump III and Micro4Controller (World Precision Instruments) at 0.5 μL/min for 6 minutes.Mice were randomly divided into groups as shown in Table 15. Anti-humanTau mouse IgG2b monoclonal antibody, clone 7G6 or mouse IgG2b isotypecontrol antibody (clone MPC11, BioXCell) in formulation buffer (25mmol/L Sodium phosphate, 0.15 mol/L NaCl, pH6.5)) were administeredintroperitoneally to reach a dose of 40 mg/kg in the groups that hadreceived seed. The same formulation buffer was administered to thenon-seed group. Dosing was performed 6-16 hours before, and 1 and 2weeks after Tau seed injection (total 3 times). The administrationvolume (10 mL/kg) was calculated from the body weight beforeadministration.

TABLE 15 Treatment Groups Group Number of Study No. Treatment animals‡Pharmacological 1 Non-seed + Vehicle 6 study 2 Tau seed + Control IgG 113 Tau seed + 7G6 11 “Non-seed” represents injection of solution (100mmol/L sodium acetate, pH 7.0) into left hippocampus , and “Tau seed”represents injection of 1.5 mg/mL Tau seed solution into lefthippocampus . Control IgG = Mouse IgG2b isotype control antibody, 7G6 =Anti-human tau mouse IgG2b monoclonal antibody. ‡Tissue from anadditional five animals in the non-seed group and 11 animals for bothtreatment groups that received seed was processed by adding buffercontaining sarkosyl to the tissue directly instead of RIPA buffer. Theseadditional animals were therefore not included in the data analysis. Areduction in insoluble Tau (after extracting with buffer containingsarkosyl twice) was still observed, however, in these additionalanimals.

All mice were deeply anesthetized with a combination anesthetic (M/M/B:prepared with 0.9 mg/kg of medetomidine, 12.0 mg/kg of midazolam, and 15mg/kg of butorphanol), and plasma and cerebrospinal fluid (CSF) werecollected. Then, the cortex and hippocampus from both sides (ipsilateraland contralateral) were separately dissected following intracardiacperfusion with saline. Brain tissues were immediately frozen in liquidnitrogen and stored at −80° C.

Dissected brain tissues were homogenized in 19 volumes (tissueweight/volume) of extraction buffer (“RIPA buffer”) containing 50 mmol/LTris-HCl (pH7.5) (Invitrogen), 5 mmol/L EDTA (Nippon Gene), 1 mmol/LEGTA (Nacalai Tesque), 1% NP-40 Alternative (EMD Millipore), 0.25%Sodium Deoxycholate (Bio world), 0.1 mol/L NaCl, 0.5 mmol/L PMSF (SigmaAldrich), 1× PhosSTOP™ (Roche), and 1× Complete EDTA(−) (Roche).Homogenates were centrifuged at 163,000 g at 4° C. for 20 minutes andthe pellet was resuspended in 10 volumes (tissue weight/volume) ofbuffer containing 10 mmol/L Tris-HCl (pH7.5), 0.5 mol/L NaCl, 1 mmol/LEGTA, 10% sucrose (Wako Pure Chemical), and 1% sarkosyl prior tosonication. Sarkosyl-treated samples were incubated at 37° C. for 60minutes, and then centrifuged at 163,000 g at 4° C. for a further 20minutes. Finally, 10 volumes of PBS (Gibco) was added to the pelletwhich was subsequently sonicated. This formed the sarkosyl-insolublefraction.

The amount of Tau protein in the sarkosyl-insoluble fraction wasquantified by Western blot analysis. Sarkosyl-insoluble fractions weresolubilized in NuPAGE™ LDS sample buffer (Novex) and NuPAGE™ samplereducing agent (Invitrogen), heated at 80° C. for 10 minutes, andseparated using 12.5% polyacrylamide gels (DRC). Proteins weretransferred to 0.2 μm PVDF membranes (Bio-Rad) and blots were blocked in2.5% skimmed milk (Yukijirushi) in TBS (Takara) containing 0.05% Tween(Nacalai tesque) for 1 hour at room temperature. After blocking, blotswere probed with the human-specific monoclonal anti-Tau antibody HT7(1:1000, Thermo Fisher Scientific) in blocking buffer for 1 hour at roomtemperature. The blots were washed in TB S-T for 30 minutes and thenincubated with HRP-conjugated anti-mouse IgG (1:2000, GE healthcare) fora further 1 hour at room temperature. Secondary antibody was removed andblots were washed as described above. Tau proteins were detected bychemiluminescent horseradish peroxidase (HRP) substrate (MerckMillipore) and quantified using the Fusion FX and FusionCapt version16.15 (Vilber-Lourmat, France). To determine the amount of Tau, serialdilutions of Tau standards derived from the originatingsarkosyl-insoluble fraction of P301S spinal cord (1, 2, 5, 10, 20Arbitrary Unit [AU], 1 AU is equivalent to the band density of human Tauprotein detected by HT7 antibody in sarkosyl insoluble fraction from 7μg of spinal cord) were loaded onto each gel. The data calculated asless than 1 AU (detection limit) was expressed as 0.5 AU.

Data are expressed as the mean±SEM. The differences insarkosyl-insoluble Tau between the Non-seed, control IgG-treated and7G6-treated groups were analyzed by 1-way analysis of variance (ANOVA)followed by Fisher's LSD test. A value of P<0.05 (two sided) wasconsidered statistically significant. Statistical analyses wereperformed using the GraphPad Prism version 7.02 (GraphPad Software).

Results

The effect of 7G6 on sarkosyl-insoluble Tau induced by intra-hippocampalTau seed injection was examined in both ipsilateral (injection side) andcontralateral cortex and hippocampus, separately. As shown in FIGS.30A-30D, 7G6 significantly suppressed the increase of sarcosyl-insolubleTau in the contralateral hippocampus compared with control IgG (FIG.30A), but showed no significant effects in other regions (FIGS. 30B,30C, and 30D). This suggests that 7G6 was able to prevent Tautransmission in this in vivo model.

Example 18: 7G6-HCzu25-LCzu18 Translational Biomarker Data

Male cynomolgus monkeys were treated with vehicle or 7G6-HCzu25-LCzu18antibody (10, 30, and 100 mg/kg: 3 animals/dose) by intermittentintravenous administration once weekly for 4 weeks. MTBR-Tau (anyisoform of full length or truncated Tau containing the MTBR) bound to7G6-HCzu25-LCzu18 antibody (“Bound MTBR-Tau”) and unbound form (“FreeMTBR-Tau”) in the cerebrospinal fluid (“CSF”) collected from each monkeywere separated by a Protein A column and analyzed by liquidchromatography coupled with mass spectrometry (LC/MS). LC/MS analysiswas performed using UltiMate™ 3000 Nano LC system coupled to OrbitrapFusion™ Lumos™ Tribrid™ mass spectrometer (Thermo Fisher Scientific, SanJose, CA) with needle column (3 μm C18 particle, 150 mm length, 100 μminner diameter). A spray voltage of 2000 V was applied through ametallic tee connector. The flow rate was 500 nL/min. The mobile phasesconsisted of (A) 0.5% acetic acid in 4% acetonitrile and (B) 0.5% aceticacid in 80% acetonitrile and a multi-step linear gradient of 1% to 1% Bfor min, 1% to 37% B for 15 min, 37% to 68% B for 5 min, 68% to 99% Bfor 1 min and 99% to 99% B for 4 min was employed to elute the analyteand then equilibrated by the initial condition, 1% B. A specific peptidecontaining 7G6-HCzu25-LCzu18 antibody epitope was measured by LC/MS as aproxy of MTBR-Tau. The amount of MTBR-Tau was expressed as thechromatographic peak area ratio of the specified peptide (Light) and itsinternal standard (Heavy), isotope-labelled peptide.

As shown in FIG. 31A, the amount of bound MTBR-Tau in CSF increased withtreatment of the 7G6-HCzu25-LCzu18 antibody in a dose-dependent manner,whereas the amount of free MTBR-Tau in monkey CSF decreased also withdose-dependency (FIG. 31B). This suggests in vivo target engagement ofthe 7G6-HCzu25-LCzu18 antibody in monkey CSF.

7G6-HCzu25-LCzu18 antibody was also spiked into human CSF at 10, 100,500, 1000 or 2000 ng/mL. Then, MTBR-Tau bound by 7G6-HCzu25-LCzu18 wasassayed by liquid chromatography coupled with mass spectrometry (LC/MS)in the same way as described above. As shown in FIG. 32 , the amount ofthe bound MTBR-Tau in human CSF increased by treatment of7G6-HCzu25-LCzu18 antibody with dose-dependency. This data alsoindicates target engagement of 7G6-HCzu25-LCzu18 antibody for MTBR-Tauin human CSF.

Example 19: Measurement of Tau Uptake in CD32A Overexpressing CHO Cells

Preparation of labelled Tau monomers and fibrils. Wild type recombinantfull length human 2N4R Tau aggregates were prepared from monomers asdescribed for the P301S protein in Example 17. Prior to labelling,aggregates were sonicated to generate the fibrils used in the assay.Both Tau fibrils and monomers were fluorescently labelled using theDyLight™ 488 NETS-Ester kit (ThermoFisherScientific, Cat #46403)according to the manufacturer's instructions with minor differencesbetween the two forms of protein: 150 μl of Tau monomer (100 μM) wasmixed with 100 μL of DyLight NETS Ester solution whereas 300 μl ofTau-441 fibril (587 μg/mL) was mixed with 66 μl of DyLight NETS Estersolution. Labelling was performed at room temperature for one hour.Excess unconjugated dye was removed with Pierce™ Dye Removal Columns(ThermoFisherScientific, Cat #22858, lot #SL260099) according to themanufacturer's protocol using 125 μl of labelled Tau monomer or 122 μLof labelled fibrils. Final concentrations of labelled Tau monomers andfibrils were measured by bicinchoninic acid assay (BCA) assay, andstored at −80° C.

Cell-based assay. Frozen CHO cells stably expressing CD32a (Fc gammaRITA) were thawed rapidly in a 37° C. water bath, and placed into CHOmedium (RPMI 1640 Medium with 10% fetal bovine serum, L-Glutamine,Non-Essential Amino Acids, Sodium Pyruvate, andpenicillin/Streptomycin). Cells were seeded at 1×10⁴ cells/well (100μl/well) in a 96-well assay plate (Costar, catalog no. 3603) andincubated for 24 hours at 37° C. in 5% CO₂ atmosphere. Labelled Taumonomers and fibrils were thawed on ice and diluted to concentrations of1.5 μg/mL or 0.5 μg/mL respectively in assay buffer (RPMI 1640 media)(GIBCO, catalog no. 21875-034). Then, in a total volume of 60 μL,7G6-HCzu25-LCzu18 antibody (final concentrations: 0.3 or 3 μg/mL), humanIgG1 isotype control (BioXcell, catalog no. BE0297) (finalconcentration: 3 μg/mL) or vehicle (25 mM sodium phosphate buffer, pH6.5, containing 150 mM NaCl) were added to either form of the proteinand incubated at room temperature for one hour protected from light. CHOmedium was removed from the plates and cells were pre-treated with 90 IAof assay buffer or a polyclonal antibody Fc receptor binding inhibitor(ThermoFisher Scientific, catalog no. 16-9161-71) diluted to 100 μg/mLalso in assay buffer. Cells were then incubated for 30 min at 37° C. in5% CO₂ atmosphere. Next, relevant wells received 10⁴ of labelled Taumonomer or Tau fibril mixtures with or without antibody and plates wereincubated for a further 60 minutes again at 37° C. in a 5% CO₂atmosphere. Each treatment was performed in quintuplicate wells. Sixindependent experiments were performed for Tau monomer uptake assays andfive independent experiments were completed to measure Tau fibriluptake.

Cell fixation and staining. Following the final incubation period, cellswere fixed in 4% paraformaldehyde for 30 min at room temperature. Eachwell was then washed with 100 μL of water and replaced by 70 μL ofHoechst staining buffer (Triton X-100 solution (final concentration:0.2%) and Hoechst solution (final concentration: 0.02%)). The plate wascovered and incubated for 30 minutes at room temperature with protectionfrom light. The staining buffer was then removed and each well waswashed twice more with 100 lit of water.

Cell imaging. Fluorescence images of each well were obtained using aCellomics high content imaging system (ThermoFisherScientific). Thetotal intensity of labelled Tau and the number of Hoechst positive cellsin each well were recorded and analysed using the Thermo Scientific HCSStudio (ThermoFisherScientific) software.

Data Analysis. The mean of total intensity of Tau signal per cell wasmeasured and the Tau uptake effect was calculated using the followingformulas in the TIBCO spotfire software program:

Tau uptake effect (% of control)=T ₁ /C ₁×100, where

-   -   T₁: Total intensity of DyLight 488 NHS conjugated Tau signal per        cells in the antibody treated sample, and    -   C₁: Total intensity of DyLight 488 NHS conjugated Tau signal per        cells in the 7G6-HCzu25-LCzu18 (30 μg/mL) treated sample.

Statistical Analysis. Data are expressed as the mean±SEM. Statisticalanalyses were performed using ONE-Way ANOVA test in the GraphPad Prismversion 7.02 (GraphPad Software) **** p<0.0001, ** p<0.01, * p<0.05.

FIGS. 33A and 33B show the efficacy of Tau monomer or fibril uptake,respectively, in CHO cells overexpressing CD32A. 7G6-HCzu25-LCzu18antibody (3 μg/mL) significantly increased Tau monomer uptake comparedto human IgG1 control (3 μg/mL) (FIG. 33A). Likewise, 7G6-HCzu25-LCzu18antibody (0.3 and 3 μg/mL) also significantly increased Tau fibriluptake compared to human IgG1 control (3 μg/mL) (FIG. 33B). In bothcases, FcR inhibitor treatment significantly blocked the effect of7G6-HCzu25-LCzu18 antibody-induced Tau uptake in this cell assay system.

What is claimed:
 1. A labeled antibody or antigen-binding fragmentcomprising a monoclonal antibody, or an antigen-binding fragmentthereof, that specifically binds a human Tau, wherein the antibodycomprises: a heavy chain variable domain (HCVD) comprising SEQ ID NO:268 and a light chain variable domain (LCVD) comprising SEQ ID NO: 465;a HCVD comprising SEQ ID NO: 268 and a LCVD comprising SEQ ID NO: 581; aHCVD comprising SEQ ID NO: 384 and a LCVD comprising SEQ ID NO: 545; aHCVD comprising SEQ ID NO: 393 and a LCVD comprising SEQ ID NO: 545; aHCVD comprising SEQ ID NO: 402 and a LCVD comprising SEQ ID NO: 545; aHCVD comprising SEQ ID NO: 384 and a LCVD comprising SEQ ID NO: 572; aHCVD comprising SEQ ID NO: 393 and a LCVD comprising SEQ ID NO: 572; ora HCVD comprising SEQ ID NO: 196 and a LCVD comprising SEQ ID NO: 411.2. The labeled antibody or antigen-binding fragment of claim 1comprising a fluorescent label, chromophoric label, electron-denselabel, chemiluminescent label, radioactive labels, enzyme, or detectableligand.
 3. A nucleic acid molecule encoding a monoclonal antibody, or anantigen-binding fragment thereof, that specifically binds a human Tau,wherein the antibody comprises: a heavy chain variable domain (HCVD)comprising SEQ ID NO: 268 and a light chain variable domain (LCVD)comprising SEQ ID NO: 465; a HCVD comprising SEQ ID NO: 268 and a LCVDcomprising SEQ ID NO: 581; a HCVD comprising SEQ ID NO: 384 and a LCVDcomprising SEQ ID NO: 545; a HCVD comprising SEQ ID NO: 393 and a LCVDcomprising SEQ ID NO: 545; a HCVD comprising SEQ ID NO: 402 and a LCVDcomprising SEQ ID NO: 545; a HCVD comprising SEQ ID NO: 384 and a LCVDcomprising SEQ ID NO: 572; a HCVD comprising SEQ ID NO: 393 and a LCVDcomprising SEQ ID NO: 572; or a HCVD comprising SEQ ID NO: 196 and aLCVD comprising SEQ ID NO:
 411. 4. A vector comprising the nucleic acidmolecule of claim
 3. 5. A cell that expresses the nucleic acid moleculeof claim
 3. 6. A method of producing an anti-Tau antibody orantigen-binding fragment comprising culturing a cell according to claim5 under conditions suitable for producing the antibody orantigen-binding fragment.
 7. The method according to claim 6 furthercomprising recovering the antibody or antigen-binding fragment.
 8. Amethod for decreasing sarkosyl-insoluble Tau levels in a subject in needthereof, the method comprising administering to the subject a monoclonalantibody, or an antigen-binding fragment thereof, that specificallybinds a human Tau, wherein the antibody comprises: a heavy chainvariable domain (HCVD) comprising SEQ ID NO: 268 and a light chainvariable domain (LCVD) comprising SEQ ID NO: 465; a HCVD comprising SEQID NO: 268 and a LCVD comprising SEQ ID NO: 581; a HCVD comprising SEQID NO: 384 and a LCVD comprising SEQ ID NO: 545; a HCVD comprising SEQID NO: 393 and a LCVD comprising SEQ ID NO: 545; a HCVD comprising SEQID NO: 402 and a LCVD comprising SEQ ID NO: 545; a HCVD comprising SEQID NO: 384 and a LCVD comprising SEQ ID NO: 572; a HCVD comprising SEQID NO: 393 and a LCVD comprising SEQ ID NO: 572; or a HCVD comprisingSEQ ID NO: 196 and a LCVD comprising SEQ ID NO:
 411. 9. A method forinhibiting Tau aggregation in a subject in need thereof, the methodcomprising administering to the subject a monoclonal antibody, or anantigen-binding fragment thereof, that specifically binds a human Tau,wherein the antibody comprises: a heavy chain variable domain (HCVD)comprising SEQ ID NO: 268 and a light chain variable domain (LCVD)comprising SEQ ID NO: 465; a HCVD comprising SEQ ID NO: 268 and a LCVDcomprising SEQ ID NO: 581; a HCVD comprising SEQ ID NO: 384 and a LCVDcomprising SEQ ID NO: 545; a HCVD comprising SEQ ID NO: 393 and a LCVDcomprising SEQ ID NO: 545; a HCVD comprising SEQ ID NO: 402 and a LCVDcomprising SEQ ID NO: 545; a HCVD comprising SEQ ID NO: 384 and a LCVDcomprising SEQ ID NO: 572; a HCVD comprising SEQ ID NO: 393 and a LCVDcomprising SEQ ID NO: 572; or a HCVD comprising SEQ ID NO: 196 and aLCVD comprising SEQ ID NO:
 411. 10. A method of treating a Tauopathy ina subject in need thereof, the method comprising: administering to thesubject a monoclonal antibody, or an antigen-binding fragment thereof,that specifically binds a human Tau, wherein the antibody comprises: aheavy chain variable domain (HCVD) comprising SEQ ID NO: 268 and a lightchain variable domain (LCVD) comprising SEQ ID NO: 465; a HCVDcomprising SEQ ID NO: 268 and a LCVD comprising SEQ ID NO: 581; a HCVDcomprising SEQ ID NO: 384 and a LCVD comprising SEQ ID NO: 545; a HCVDcomprising SEQ ID NO: 393 and a LCVD comprising SEQ ID NO: 545; a HCVDcomprising SEQ ID NO: 402 and a LCVD comprising SEQ ID NO: 545; a HCVDcomprising SEQ ID NO: 384 and a LCVD comprising SEQ ID NO: 572; a HCVDcomprising SEQ ID NO: 393 and a LCVD comprising SEQ ID NO: 572; or aHCVD comprising SEQ ID NO: 196 and a LCVD comprising SEQ ID NO: 411,under conditions effective to treat the Tauopathy in the subject. 11.The method according to claim 10, wherein the Tauopathy is Alzheimer'sdisease, frontotemporal dementia, or progressive supranuclear palsy. 12.The method according to claim 11, wherein the frontotemporal dementia isPick's disease.